JP2021530554A - Methods and ACVR1 Inhibitors for Treatment of Diseases with Abnormal ACVR1 Expression - Google Patents

Abstract

Formula (I), the stereoisomers thereof, tautomers, pharmaceutically acceptable salts, and prodrugs are included, wherein R1, R2, R3, and R4 are defined herein. Disclosed is a method for treating a disease of interest in need thereof by administering an ACVR1 inhibitor having (I). Subjects who can benefit from the treatment may have mutations in their ACVR1 gene. Various diseases, including cancer (eg, diffuse true pontine glioma (DIPG)) and genetic disorders (eg, progressive ossifying fibrodysplasia (FOP)), are described using the methods described. Can be treated.

Description

Cross-references This application claims the interests of US Provisional Application No. 62 / 703,862, filed July 26, 2018, which is incorporated herein by reference in its entirety.

INDUSTRIAL APPLICABILITY The present disclosure provides therapeutic uses of a compound having activity as an ACVR1 inhibitor and methods of treatment including administration of the compound. The present disclosure also provides a pharmaceutical composition comprising a compound having activity as an ACVR1 inhibitor. Furthermore, the present disclosure provides a novel form of a compound having activity as an ACVR1 inhibitor.

Background of the Invention Bone morphogenetic protein (BMP) is a pleiotropic growth factor that plays an essential role in coordinating tissue mechanisms throughout various organs in the body. BMP ligands interact with bone morphogenetic protein receptors (BMPRs), which belong to the transforming growth factor beta (TGF-b) superfamily of serine / threonine kinase receptors (Ikushima, H. and K. Miyazono, Biology of Transforming Growth Factor-beta Signalin. Curr Pharm Biotechnol, 2011, which is incorporated herein by reference with respect to such background teachings). The ligand binds to the type II receptor and then replenishes the type I receptor to form a heteromer complex. As a complex, the type II receptor phosphorylates the type I receptor, which becomes active and phosphorylates downstream signaling molecules. The downstream action of activating these receptors is primarily carried out by the SMAD family of proteins. SMAD becomes phosphorylated and transmits signals from the cell membrane to the nucleus, where it functions as a transcription factor for regulating gene expression (Massague, J., J. Seoane, and D. Wotton, Smad transcription). factors. Genes Dev, 2005. 19 (23): p. 2783-810, which is incorporated herein by reference with respect to such background teachings).

In individuals with chronic diseases such as cancer and inflammation, BMP signaling is constitutively activated leading to anemia. This condition is commonly referred to as anemia of chronic disease (ACD), which is a debilitating symptom associated with cancer patients (Cullis, JO, Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol, 2011. 154 (3): p. 289-300, which is incorporated herein by reference with respect to such background teachings). Chronic anemia in cancer patients results in extreme weakness and fatigue, resulting in an inadequate quality of life for these individuals. In these patients, BMP signaling through two BMP type I receptors, ALK2 (also known as ACVR1 as described) and ALK3, induces liver expression of a peptide hormone called hepcidin. (Steinbicker, AU, et al., Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood, 2011. 118 (15): p. 4224-30, which relates to the teaching of such background. , Incorporated herein by reference).

Hepcidin reduces serum iron levels by promoting the breakdown of the iron transporter, ferroportin, resulting in increased iron storage in macrophages and other cell types, iron for hemoglobin and red blood cell (RBC) function. Will not be available. Supplementing the patient's iron intake does not reverse the ACD, as only the iron digested due to the activated BMP pathway and high serum hepcidin levels is stored. Currently, ACD in cancer is controlled by limiting the physical activity of the patient, and blood transfusions are used in the most severe cases. Inhibition of BMP signaling in these patients can make a real difference in their quality of life and ultimately can have a positive effect on how they respond to treatment, radiation or surgery. Steinbicker, AU, et al., Inhibition of bone morphogenetic protein signaling immunos anemia associated with inflammation. Blood, 2011. 117 (18): p. 4915-23; Coyne, DW, Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int, 2011. 80 (3): p. 240-4; Theurl, I., et al., Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats. Blood, 2011, Each such background teaching is incorporated herein by reference).

In addition to its function in ACD, BMP signaling plays a vital role in the growth and metastasis of cancer cells, especially in breast cancer, prostate cancer, and other cancers that frequently metastasize to bone (Ye, L., MD Mason, and WG Jiang, Bone morphogenetic protein and bone metastasis, implication and therapeutic potential. Front Biosci, 2011. 16: p. 865-97). BMP and BMPR are more highly expressed in metastatic breast cancer cells than those with low metastasis, and are also expressed in prostate cancer cells that cause osteosclerotic bone metastases (Bobinac, D., et al., Expression of). bone morphogenetic proteins in human metastatic prostate and breast cancer. Croat Med J, 2005. 46 (3): p. 389-96). In addition to affecting the invasiveness and metastasis of cancer cells, the BMP pathway has also been shown to affect the bone microenvironment. Studies have shown that inhibition of BMP signaling significantly reduces bone tumor burden and osteolytic disease in a preclinical model of prostate cancer bone metastasis. These results suggest that BMP inhibitors may have uses in the prevention of bone metastases.
In addition, BMP inhibitors have the potential to treat multiple disease signs other than cancer. ACD is a catastrophic condition that affects individuals with other diseases, including rheumatoid arthritis, systemic lupus, chronic kidney disease, and many other inflammatory diseases. In addition, a rare pediatric hereditary disease called progressive ossifying fibrodysplasia (FOP) has been shown to be caused by activating mutations in the alk2 gene (Kaplan, FS, et). al., Investigations of activated ACVR1 / ALK2, a bone morphogenetic protein type I receptor, that causes fibrodysplasia ossificans progressiva. Methods Enzymol, 2010. 484: p. 357-73). Mutations in ALK2 in this disease cause ossification when fibrous tissue (muscles, tendons, ligaments, etc.) is damaged. Studies conducted in animal models of FOP suggest that inhibition of ALK2 reduces FOP-related "relapse" and prevents ossification of the model's repair tissue.

Ikushima, H. and K. Miyazono, Biology of Transforming Growth Factor-beta Signalin. Curr Pharm Biotechnol, 2011 Massague, J., J. Seoane, and D. Wotton, Smad transcription factors. Genes Dev, 2005. 19 (23): p. 2783-810 Cullis, J.O., Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol, 2011. 154 (3): p. 289-300 Steinbicker, A.U., et al., Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood, 2011. 118 (15): p. 4224-30 Steinbicker, A.U., et al., Inhibition of bone morphogenetic protein signaling potentiates anemia associated with inflammation. Blood, 2011. 117 (18): p. 4915-23 Coyne, D.W., Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int, 2011. 80 (3): p. 240-4 Theurl, I., et al., Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats. Blood, 2011 Ye, L., M.D. Mason, and W.G. Jiang, Bone morphogenetic protein and bone metastasis, implication and therapeutic potential. Front Biosci, 2011. 16: p. 865-97 Bobinac, D., et al., Expression of bone morphogenetic proteins in human metastatic prostate and breast cancer. Croat Med J, 2005. 46 (3): p. 389-96 Kaplan, F.S., et al., Investigations of activated ACVR1 / ALK2, a bone morphogenetic protein type I receptor, that causes fibrodysplasia ossificans progressiva. Methods Enzymol, 2010. 484: p. 357-73

の化合物またはその結晶塩を投与することを含む、方法を提供する。 Summary of the Disclosure In one embodiment, the disclosure is a method of treating diffuse true pontine glioma (DIPG) in a subject requiring treatment of diffuse true pontine glioma (DIPG). Therapeutic effective dose formula (2):

Provided are methods comprising administering a compound of, or a crystalline salt thereof.

In one aspect, the crystalline salt is an acid addition salt. In one aspect, the acid addition salt is a hydrochloride salt. In one aspect, the hydrochloride salt is monovalent. In one aspect, the crystalline salt form is anhydrous. In one aspect, the subject is a pediatric patient. In one aspect, the subject is about 1 week to about 22 years old. In one aspect, the subject is about 18 years or younger. In one aspect, the subject is about 10 years or younger. In one aspect, the subject is about 8 years or younger. In one aspect, the subject is about 6 years or younger. In one aspect, DIPG is a newly diagnosed or recurrent. In one aspect, DIPG is characterized as a pontine tumor histologically diagnosed as invasive glioma grade II through IV. In one aspect, the method further comprises administering radiation therapy. In one aspect, the administration of radiation is performed prior to the administration of the compound or a crystalline salt thereof. In one aspect, the administration of radiation is performed after administration of the compound or a crystalline salt thereof. In one aspect, the administration of radiation takes place both before and after administration of the compound or its crystalline salt. In one aspect, the method further comprises administering one or more additional therapeutic agents. In one aspect, the radiation can be administered as a component agent. In one aspect, administration of the compound or crystalline salt thereof reduces or alleviates one or more signs or symptoms associated with DIPG. In one aspect, one or more signs or symptoms are changes in conversation or conversation patterns, loss of ability to move one side of the subject's face or body, loss of balance, loss of coordination, gait or motor problems, Select from the group consisting of visual problems, hearing problems, headache, nausea, vomiting, abnormal drowsiness, altered energy levels, behavioral changes, and changes in school performance. In one aspect, administration of the compound or a crystalline salt thereof achieves a hate-free survival. In one aspect, hate-free survival is one month or longer, two months or longer, three months or longer, four months or longer, five months or longer. Longer, 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, 10 months or longer, 11 months or longer, 1 year or longer, 2 years or longer, 3 years or longer, or 5 years or longer. In one aspect, the method further comprises one or more of tumor growth weight loss or cerebrospinal fluid conversion. In one aspect, the subject has a given gene profile that contains one or more mutations in the ACVR1 gene. In one aspect, one or more mutations in the ACVR1 gene are activating mutations. In one aspect, one or more mutations in the ACVR1 gene are selected from R206H, G328V, R258G, or a combination thereof and contain an amino acid substitution at one or more amino acid residues. Encode the peptide. In one aspect, the amino acid substitution in the ACVR1 polypeptide comprises R206H. In one aspect, the compound or a crystalline salt thereof is orally administered. In one aspect, the compound or crystalline salt thereof is administered at a dose ranging from about 10 mg to about 320 mg per week. In one aspect, the dose ranges from about 30 mg to about 240 mg per week. In one aspect, the dose ranges from about 60 mg to about 180 mg per week. In one aspect, the dose ranges from about 30 mg to about 120 mg per week. In one aspect, the dose ranges from about 60 mg to about 120 mg per week. In one aspect, the dose is about 60 mg per week. In one aspect, the dose is about 90 mg per week. In one aspect, the dose is about 120 mg per week. In one aspect, the dose is about 180 mg per week. In one aspect, the dose is about 210 mg per week. In one aspect, the dose is about 240 mg per week. In one aspect, the compound or crystalline salt thereof is about 320 mg or less, about 240 mg or less, about 210 or less, about 180 or less, about 120 or less. , About 90 or less, about 60 or less, or about 30 or less weekly doses. In one aspect, the dose is about 60 mg or less per week. In one aspect, the dose is about 90 mg or less per week. In one aspect, the dose is about 120 mg or less per week. In one aspect, the dose is about 180 mg or less per week. In one aspect, the dose is about 210 mg or less per week. In one aspect, the dose is about 240 mg or less per week. In one aspect, the dose is administered once a week. In one aspect, the dose is a partial dose of 2 or more times over a week of cool, a partial dose of 3 or more times, a partial dose of 4 or more times, 5 times or more. It is administered in excess of partial doses, 6 or more partial doses, or daily partial doses. In one aspect, the subject is a pediatric patient and the dose is between about 80% and 100% of the dose range. In one aspect, the dose is adjusted to 80%, 85%, 90%, or 95% of the dose range. In one aspect, the dose ranges from about 8 mg to about 320 mg per week. In one aspect, the dose ranges from about 24 mg to about 240 mg per week. In one aspect, the dose ranges from about 24 mg to about 120 mg per week. In one aspect, the dose ranges from about 48 mg to about 120 mg per week. In one aspect, the dose ranges from about 72 mg to about 120 mg per week. In one aspect, the dose ranges from about 96 mg to about 120 mg per week. In one aspect, the subject has a predetermined hepcidin level of at least about 0.1 ng / mL. In one aspect, predetermined hepcidin levels range from about 10 ng / mL to about 200 ng / mL. In one aspect, the method further comprises determining the hepcidin level of interest after administration of the compound or crystalline salt thereof. In one aspect, the method further comprises determining the transferrin saturation level of the subject after administration of the compound or crystalline salt thereof. In one aspect, the transferrin saturation level is less than about 50%. In one aspect, the transferrin saturation level is less than about 45%. In one aspect, the transferrin saturation level is less than about 40%. In one aspect, the compound or crystalline salt thereof is administered over one or more treatment cycles, each cycle comprising 4 weeks. In one aspect, the method further comprises one or more rest days between treatment cycles. In one aspect, the rest day is selected from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks.

の化合物またはその結晶塩を投与することを含み、化合物は、週当たり約１０ｍｇから約３２０ｍｇに及ぶ用量で投与される、方法を提供する。一態様では、用量は、週当たり約３０ｍｇから約２４０ｍｇに及ぶ。一態様では、用量は、週当たり約６０ｍｇから約１８０ｍｇに及ぶ。一態様では、用量は、週当たり約３０ｍｇから約１２０ｍｇに及ぶ。一態様では、用量は、週当たり約６０ｍｇから約１２０ｍｇに及ぶ。一態様では、用量は、週当たり約６０ｍｇである。一態様では、用量は、週当たり約９０ｍｇである。一態様では、用量は、週当たり約１２０ｍｇである。一態様では、用量は、週当たり約１８０ｍｇである。一態様では、用量は、週当たり約２１０ｍｇである。一態様では、用量は、週当たり約２４０ｍｇである。一態様では、化合物またはその結晶塩は、約３２０ｍｇもしくはそれよりも少ない、約２４０ｍｇもしくはそれよりも少ない、約２１０もしくはそれよりも少ない、約１８０もしくはそれよりも少ない、約１２０もしくはそれよりも少ない、約９０もしくはそれよりも少ない、約６０もしくはそれよりも少ない、または約３０もしくはそれよりも少ない１週用量で投与される。一態様では、用量は、週当たり約６０ｍｇまたはそれよりも少ない。一態様では、用量は、週当たり約９０ｍｇまたはそれよりも少ない。一態様では、用量は、週当たり約１２０ｍｇまたはそれよりも少ない。一態様では、用量は、週当たり約１８０ｍｇまたはそれよりも少ない。一態様では、用量は、週当たり約２１０ｍｇまたはそれよりも少ない。一態様では、用量は、週当たり約２４０ｍｇまたはそれよりも少ない。一態様では、対象が小児患者であり、用量は、用量範囲の約８０％から１００％の間である。一態様では、用量は、用量範囲の約８０％、８５％、９０％、または９５％である。一態様では、用量は、週当たり約８ｍｇから約３２０ｍｇに及ぶ。一態様では、用量は、週当たり約２４ｍｇから約２４０ｍｇに及ぶ。一態様では、用量は、週当たり約２４ｍｇから約１２０ｍｇに及ぶ。一態様では、用量は、週当たり約４８ｍｇから約１２０ｍｇに及ぶ。一態様では、用量は、週当たり約７２ｍｇから約１２０ｍｇに及ぶ。一態様では、用量は、週当たり約９６ｍｇから約１２０ｍｇに及ぶ。一態様では、用量は、１週間に１回投与される。一態様では、用量は、１週間のクールにわたって２回の部分用量で投与される。一態様では、用量は、１週間のクールにわたって３回の部分用量で投与される。一態様では、用量は、１週間のクールにわたって４回の部分用量で投与される。一態様では、用量は、１週間のクールにわたって５回の部分用量で投与される。一態様では、用量は、１週間のクールにわたって６回の部分用量で投与される。一態様では、用量は、毎日の部分用量で投与される。一態様では、対象は、ＡＣＶＲ１遺伝子中に１つまたはそれより多くの変異を含む所定の遺伝子プロファイルを有する。一態様では、ＡＣＶＲ１遺伝子中の１つまたはそれより多くの変異は、活性化変異である。一態様では、ＡＣＶＲ１遺伝子中の１つまたはそれより多くの変異は、Ｒ２０６Ｈ、Ｇ３２８Ｖ、Ｒ２５８Ｇ、またはこれらの組合せから選択される、１つまたはそれより多くのアミノ酸残基におけるアミノ酸置換を含むＡＣＶＲ１ポリペプチドをコードする。一態様では、ＡＣＶＲ１ポリペプチド中のアミノ酸置換は、Ｒ２０６Ｈを含む。一態様では、化合物またはその結晶塩は、経口投与される。一態様では、疾患または障害は、びまん性真性橋膠腫、グレードＩＩからＩＶの浸潤性グリオーマと組織学的診断がなされた脳橋腫瘍、固形腫瘍、進行性骨化性線維異形成症、および慢性疾患の貧血症の１つまたは複数から選択される。一態様では、疾患または障害は、びまん性真性橋膠腫である。一態様では、疾患または障害は、浸潤性グリオーマ−グレードＩＩからＩＶと組織学的診断がなされた脳橋腫瘍である。一態様では、疾患または障害は、固形腫瘍である。一態様では、疾患または障害は、進行性骨化性線維異形成症である。一態様では、疾患または障害は、慢性疾患の貧血症である。一態様では、化合物またはその結晶塩は、固体用量製剤として投与される。一態様では、化合物またはその結晶塩は、液体用量製剤として投与される。一態様では、対象は、用量の任意の修正を決定するためにヘプシジンレベルに関してモニタリングされる。一態様では、対象は、１つまたはそれより多くの臓器における化合物の蓄積に関してモニタリングされる。一態様では、結晶塩は、酸付加塩である。一態様では、酸付加塩は、塩酸塩である。一態様では、塩酸塩は、１価である。一態様では、結晶塩形態は、無水物である。 In one embodiment, the present disclosure is a method for treating a disease or disorder that is susceptible to inhibition of ACVR1, and the method requires treatment of a disease or disorder that is susceptible to inhibition of ACVR1. For the subject, the therapeutically effective amount formula (2):

Provided is a method of administering a compound of, or a crystalline salt thereof, in which the compound is administered at a dose ranging from about 10 mg to about 320 mg per week. In one aspect, the dose ranges from about 30 mg to about 240 mg per week. In one aspect, the dose ranges from about 60 mg to about 180 mg per week. In one aspect, the dose ranges from about 30 mg to about 120 mg per week. In one aspect, the dose ranges from about 60 mg to about 120 mg per week. In one aspect, the dose is about 60 mg per week. In one aspect, the dose is about 90 mg per week. In one aspect, the dose is about 120 mg per week. In one aspect, the dose is about 180 mg per week. In one aspect, the dose is about 210 mg per week. In one aspect, the dose is about 240 mg per week. In one aspect, the compound or crystalline salt thereof is about 320 mg or less, about 240 mg or less, about 210 or less, about 180 or less, about 120 or less. , About 90 or less, about 60 or less, or about 30 or less weekly doses. In one aspect, the dose is about 60 mg or less per week. In one aspect, the dose is about 90 mg or less per week. In one aspect, the dose is about 120 mg or less per week. In one aspect, the dose is about 180 mg or less per week. In one aspect, the dose is about 210 mg or less per week. In one aspect, the dose is about 240 mg or less per week. In one aspect, the subject is a pediatric patient and the dose is between about 80% and 100% of the dose range. In one aspect, the dose is about 80%, 85%, 90%, or 95% of the dose range. In one aspect, the dose ranges from about 8 mg to about 320 mg per week. In one aspect, the dose ranges from about 24 mg to about 240 mg per week. In one aspect, the dose ranges from about 24 mg to about 120 mg per week. In one aspect, the dose ranges from about 48 mg to about 120 mg per week. In one aspect, the dose ranges from about 72 mg to about 120 mg per week. In one aspect, the dose ranges from about 96 mg to about 120 mg per week. In one aspect, the dose is administered once a week. In one aspect, the dose is administered in two partial doses over a week of cool. In one aspect, the dose is administered in 3 partial doses over a week of cool. In one aspect, the dose is administered in 4 partial doses over a week of cool. In one aspect, the dose is administered in 5 partial doses over a week of cool. In one aspect, the dose is administered in 6 partial doses over a week of cool. In one aspect, the dose is administered in daily partial doses. In one aspect, the subject has a given gene profile that contains one or more mutations in the ACVR1 gene. In one aspect, one or more mutations in the ACVR1 gene are activating mutations. In one aspect, one or more mutations in the ACVR1 gene are selected from R206H, G328V, R258G, or a combination thereof and contain an amino acid substitution at one or more amino acid residues. Encode the peptide. In one aspect, the amino acid substitution in the ACVR1 polypeptide comprises R206H. In one aspect, the compound or crystalline salt thereof is orally administered. In one aspect, the disease or disorder is diffuse true pontine glioma, pontine tumor histologically diagnosed as grade II to IV invasive glioma, solid tumor, progressive ossifying fibrous dysplasia, and. It is selected from one or more of chronic anemia. In one aspect, the disease or disorder is diffuse true pontine glioma. In one aspect, the disease or disorder is a pontine tumor histologically diagnosed as invasive glioma-grade II to IV. In one aspect, the disease or disorder is a solid tumor. In one aspect, the disease or disorder is progressive ossifying fibrodysplasia. In one aspect, the disease or disorder is anemia of chronic disease. In one aspect, the compound or crystalline salt thereof is administered as a solid dose formulation. In one aspect, the compound or crystalline salt thereof is administered as a liquid dose formulation. In one aspect, the subject is monitored for hepcidin levels to determine any adjustment of the dose. In one aspect, the subject is monitored for the accumulation of compounds in one or more organs. In one aspect, the crystalline salt is an acid addition salt. In one aspect, the acid addition salt is a hydrochloride salt. In one aspect, the hydrochloride salt is monovalent. In one aspect, the crystalline salt form is anhydrous.

の化合物またはその結晶塩とを含む経口固体医薬組成物であって、化合物は、遊離塩基重量に対して約５ｍｇから約１２５ｍｇの間の力価で製剤化される、医薬組成物を提供する。 In one embodiment, the present disclosure comprises one or more pharmaceutically acceptable excipients and formula (2):

An oral solid pharmaceutical composition comprising the compound of the above or a crystalline salt thereof, wherein the compound is formulated with a titer between about 5 mg and about 125 mg based on the weight of the free base.

In one aspect, the crystalline salt is an acid addition salt. In one aspect, the acid addition salt is a hydrochloride salt. In one aspect, the hydrochloride salt is monovalent. In one aspect, the crystalline salt form is anhydrous. In one aspect, the pharmaceutical composition is a gelatin capsule. In one aspect, gelatin capsules are titered at (i) 5 mg, (ii) 25 mg, or (iii) 125 mg relative to free base weight. In one aspect, gelatin capsules are (i) 30 mg, (ii) 60 mg, (iii) 90 mg, or (iv) 120 mg relative to free base weight. In one aspect, one or more pharmaceutical excipients are selected from microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate, or a combination thereof.

の化合物またはその結晶塩と；
ａ）１種またはそれより多種の緩衝剤；
ｂ）必要に応じて、１種またはそれより多種の保存剤；
ｃ）必要に応じて、１種またはそれより多種の溶媒；
ｄ）必要に応じて、１種またはそれより多種の矯味剤；および
ｅ）必要に応じて、１種またはそれより多種のさらなるｐＨ調節剤
とを含む、経口液体医薬組成物を提供する。 In one embodiment, the present disclosure comprises formula (2) :.

With a compound of or a crystalline salt thereof;
a) One or more buffers;
b) One or more preservatives as needed;
c) One or more solvents as needed;
d) Provided are oral liquid pharmaceutical compositions comprising one or more flavoring agents as needed; and e) one or more additional pH regulators as needed.

In one aspect, the crystalline salt is an acid addition salt. In one aspect, the acid addition salt is a hydrochloride salt. In one aspect, the hydrochloride salt is monovalent. In one aspect, the crystalline salt form is anhydrous. In one aspect, the composition has a pH between about 2.0 and about 5.0. In one aspect, the composition has a pH between about 2.0 and about 3.5. In one aspect, the composition has a pH of about 2.0. In one aspect, the buffer is selected from citric acid, tartaric acid, malic acid, or acetic acid. In one aspect, the buffer is malic acid. In one aspect, the malic acid is DL-malic acid. In one aspect, the composition comprises one or more preservatives. In one aspect, the preservative is selected from benzoic acid, sodium benzoate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or propylene glycol. In one aspect, the preservative is benzoic acid. In one aspect, benzoic acid is a preservative and buffer. In one aspect, it comprises one or more flavoring agents. In one aspect, the flavoring agent is selected from sucralose, glycerin, cyclodextrin, HP-β-cyclodextrin, α-cyclodextrin, β-cyclodextrin, or a combination thereof. In one aspect, the flavoring agent is a combination of HP-β-cyclodextrin and sucralose. In one aspect, the composition comprises the compound of formula (2) or a crystalline salt thereof at a concentration of about 10 mg / mL. In one aspect, the composition comprises malic acid at a concentration of up to about 6.7 mg / mL. In one aspect, the composition comprises malic acid at a concentration of about 1.3 mg / mL. In one aspect, the composition comprises HP-β-cyclodextrin at a concentration of up to about 300 mg / mL. In one aspect, the composition comprises HP-β-cyclodextrin at a concentration of up to about 150 mg / mL. In one aspect, the composition comprises sucralose at a concentration of up to about 2.0 mg / mL. In one aspect, the composition comprises sucralose at a concentration of about 1.0 mg / mL. In one aspect, the composition comprises benzoic acid at a concentration of up to about 3.0 mg / mL. In one aspect, the composition comprises benzoic acid at a concentration of up to about 2.0 mg / mL. In one aspect, the pH is adjusted to about 2.0 with hydrochloric acid. In one aspect, the solvent is water.

Ｎ^４−（２，２’−ビピリジン−３−イル）−Ｎ^２−（３−メトキシ−４−（４−メチルピペラジン−１−イル）フェニル）ピリミジン−２，４−ジアミンの塩の結晶形態を提供する。 In one embodiment, the present disclosure is compound (2).

N ⁴ - (2,2'-bipyridine-3-yl) ^-N 2 - crystalline form of (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) salts of pyrimidine-2,4-diamine I will provide a.

In one aspect, the salt is a pharmaceutically acceptable salt. In one aspect, the pharmaceutically acceptable salt is an HCl salt. In one aspect, the crystalline form comprises form A. In one aspect, the crystalline morphology essentially consists of morphology A. In one aspect, Form A is substantially free of impurities.

In one embodiment, the present ^disclosure, N 4 - (2,2'-bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2 , 4-Diamine Anhydrous Hydrochloride, Compound Form A.

In one embodiment, the present disclosure is an x-ray diffraction pattern comprising one or more 2θ values selected from 13.53, 16.14, 17.67, 18.38, 24.96, and 28.18. (XRPD), characterized ^in, N 4 - (2,2'-bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2, The compound form A of 4-diamine anhydrous hydrochloride is provided.

In one aspect, the morphology is characterized by two or more of the listed 2θ values. In one aspect, the morphology is characterized by three or more of the listed 2θ values. In one aspect, the morphology is characterized by four or more of the listed 2θ values. In one aspect, the morphology is characterized by five or more of the listed 2θ values. In one aspect, the morphology is characterized by all six of the listed 2θ values. In one aspect, the form is further characterized by one or more 2θ values selected from 6.71, 19.25, 23.98, and 29.60. In one aspect, the morphology is characterized by two or more of the listed 2θ values. In one aspect, the morphology is characterized by three or more of the listed 2θ values. In one aspect, the morphology is characterized by all four of the listed 2θ values. In one aspect, the X-ray powder diffractometer uses the X-ray wavelength of Cu kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.5444426, with a Kα2 / Kα1 intensity ratio of 0.50. Then, the X-ray tube is set to 45 kV and 40 mA and used in the reflection mode. In one aspect, the 2θ value is within ± 0.2 2θ.

In one embodiment, the present disclosure features a 12 substantially the same x-ray diffraction pattern ^{(XRPD), N 4 - (} 2,2'- ^{bipyridine-3-yl)} -N 2 - (3- Provided is compound form A of methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2,4-diamine anhydrous hydrochloride.

In one embodiment, the present disclosure, 196.2 ° C., characterized by endotherm at one or more of 214.8 ° C., and 274.0 ^℃, N 4 - (2,2'- bipyridine - 3 is provided in compound form A of 3-yl) -N ^2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2,4-diamine anhydride.

In one embodiment, the disclosure is further characterized by peak endotherm at one or more of 198.9 ° C., 218.0 ° C., and 275.9 ° C. In one aspect, the morphology is further characterized by a starting temperature of 274.0 ° C. In one aspect, the form is further characterized by a weight loss of 1.7% up to 150 ° C.

In one embodiment, the disclosure features a substantially identical TGA-DSC thermogram and FIG ^15, N 4 - (2,2'-bipyridine-3-yl) ^-N 2 - (3- methoxy - Provided is compound form A of 4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2,4-diamine anhydrous hydrochloride.

In one embodiment, the present disclosure provides a pharmaceutical composition comprising the crystalline form of the present disclosure. In one aspect, the composition is a solid dose formulation. In a particular aspect, the solid-dose formulation is the oral solid pharmaceutical composition of the present disclosure, wherein the compound is in the crystalline form of the present disclosure. In one aspect, the composition is a liquid dose formulation. In a particular aspect, the liquid-dose formulation is the oral liquid pharmaceutical composition of the present disclosure, wherein the compound is in the crystalline form of the present disclosure.

In one embodiment, the present disclosure provides any method of the present disclosure, wherein the compound is in crystalline form of the present disclosure.

In one embodiment, the disclosure provides a pharmaceutical composition comprising the crystalline form of the present disclosure, either alone or in combination with radiation or an additional therapeutic agent. In one aspect, the composition is a solid dose formulation. In one aspect, the composition is a liquid dose formulation.

One embodiment of the present disclosure includes any method of the present disclosure, comprising administering any compound of the present disclosure.

One embodiment of the present disclosure comprises the use of any compound of the present disclosure in one or more of the treatments of the present disclosure.

One embodiment of the present disclosure comprises the preparation of a medicament according to the present disclosure for the treatment of one or more diseases or disorders disclosed herein.

One embodiment of the present disclosure includes the use of the compounds of the present disclosure in treatment.

またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有し、式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＲ^４が本明細書で定義される通りである方法を提供する。 Briefly, embodiments of the present disclosure comprise administering to a subject having a given gene profile containing one or more mutations in the ACVR1 gene a treatment regimen comprising an ACVR1 inhibitor. A method for treating a disease of interest that requires an ACVR1 inhibitor according to formula (I):

Or a stereoisomer thereof, a pharmaceutically acceptable salt, tautomer, or prodrug thereof, as ^{wherein, R 1, R 2, R} 3, and where R ⁴ is as defined herein Provides a way to be.

またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有し、式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＲ^４が本明細書で定義される通りである方法を提供する。 A further embodiment of the disclosure is a method for treating diffuse true pontine glioma (DIPG) in a subject in need thereof, comprising administering to the subject a treatment regimen containing an ACVR1 inhibitor. The ACVR1 inhibitor has the following formula (I):

Or a stereoisomer thereof, a pharmaceutically acceptable salt, tautomer, or prodrug thereof, as ^{wherein, R 1, R 2, R} 3, and where R ⁴ is as defined herein Provides a way to be.

またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有し、式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＲ^４が本明細書で定義される通りである方法を提供する。 An additional embodiment of the present disclosure treats progressive ossifying fibrodysplasia (FOP) in a subject in need thereof, comprising administering to the subject a treatment regimen comprising an ACVR1 inhibitor and a therapeutic agent. The ACVR1 inhibitor is a method for the following formula (I):

Or a stereoisomer thereof, a pharmaceutically acceptable salt, tautomer, or prodrug thereof, as ^{wherein, R 1, R 2, R} 3, and where R ⁴ is as defined herein Provides a way to be.

One embodiment of the present disclosure comprises the use of an ACVR1 inhibitor of formula (I) to treat diseases associated with aberrant ACVR1 expression (eg, mutations in the expressed protein) such as DIPG and FOP, as well. Provided.

One or more embodiments and embodiments may be incorporated into different embodiments, but are not specifically described. That is, all embodiments and embodiments may be combined in any way or combination.

These and other aspects of the disclosure will be apparent by reference to the detailed description below.

In the figure, the same reference numerals identify similar elements. The size and relative position of the elements in the figure are not necessarily drawn to scale, and some of these elements are arbitrarily magnified and positioned to improve the visibility of the figure. Moreover, the particular shape of the element being drawn is not intended to convey any information about the actual shape of the particular element, but has only been selected to facilitate recognition in the figure.

FIG. 1 presents data showing the inhibition of SMAD1 / 5 phosphorylation in BMP2-stimulated HepG2 cells by Compound 2.

2A and 2B show inhibition of hepcidin expression in HepG2 cells by Compound 2 with or without BMP-2 stimulation (FIG. 2B). 2A and 2B show inhibition of hepcidin expression in HepG2 cells by Compound 2 with or without BMP-2 stimulation (FIG. 2B).

FIG. 3 shows plasma iron levels for the group given compound 2. Black bars indicate the group to which turpentine was administered.

FIG. 4A shows the intracerebral pharmacokinetics of compound 2 delivered intravenously and orally in mice, and FIG. 4B shows the concentration of compound 2 in plasma and brain tissue. FIG. 4A shows the intracerebral pharmacokinetics of compound 2 delivered intravenously and orally in mice, and FIG. 4B shows the concentration of compound 2 in plasma and brain tissue.

FIG. 5 shows the results of pharmacokinetic and toxicity tests for Compound 2.

FIG. 6A shows the dose response curve for compound 2 in IGR-OV1 cells. Figure 6B shows a comparison _{IC 50} data relating to the seven cell lines. FIG. 6A shows the dose response curve for compound 2 in IGR-OV1 cells. Figure 6B shows a comparison _{IC 50} data relating to the seven cell lines.

FIG. 7 shows the effect of Compound 2 on tumor volume in a xenograft model.

FIG. 8 shows the activity of compound 2 on ALK2 / ACVR1 with various mutations.

FIG. 9A shows a lollipop diagram of the distribution of ACVR1 mutations in The Cancer Genome Atlas (TCGA) Pancancer and Memorial Sloan Kettering (MSK) IMPACT databases. FIG. 9B shows the distribution of chromosomal abnormalities found across various adult tumor types in the TCGA pancancer and MSK IMPACT databases. FIG. 9C shows a Kaplan-Meier curve showing that subjects with a genetic abnormality in ACVR1 have a 6-month shorter survival time than subjects without ACVR1 alterations. FIG. 9A shows a lollipop diagram of the distribution of ACVR1 mutations in The Cancer Genome Atlas (TCGA) Pancancer and Memorial Sloan Kettering (MSK) IMPACT databases. FIG. 9B shows the distribution of chromosomal abnormalities found across various adult tumor types in the TCGA pancancer and MSK IMPACT databases. FIG. 9C shows a Kaplan-Meier curve showing that subjects with a genetic abnormality in ACVR1 have a 6-month shorter survival time than subjects without ACVR1 alterations. FIG. 9A shows a lollipop diagram of the distribution of ACVR1 mutations in The Cancer Genome Atlas (TCGA) Pancancer and Memorial Sloan Kettering (MSK) IMPACT databases. FIG. 9B shows the distribution of chromosomal abnormalities found across various adult tumor types in the TCGA pancancer and MSK IMPACT databases. FIG. 9C shows a Kaplan-Meier curve showing that subjects with a genetic abnormality in ACVR1 have a 6-month shorter survival time than subjects without ACVR1 alterations.

FIG. 10 shows the results of an in vitro sensory analysis of an oral liquid preparation containing Compound 2. Bitterness was measured and converted for comparison with kinin.

FIG. 11 shows the results of an in vitro sensory analysis of an oral liquid preparation containing Compound 2. Bitterness was measured and converted for comparison with kinin.

FIG. 12 is an XRPD pattern of compound 2-mono-HCl salt form A (812608-08-A1).

13A and 13B are superpositions of XRPD in the form of compound 2 HCl salt crystals. 13A and 13B are superpositions of XRPD in the form of compound 2 HCl salt crystals.

FIG. 14 is a superposition of XRPDs of compound 2 HCl salt form A batch to demonstrate equivalence.

FIG. 15 shows the TGA / DSC curve of Compound 2 HCl Form A (812608-12-A).

FIG. 16 shows the DSC of compound 2 HCl form A (812608-12A_218C) after heating.

FIG. 17 shows the superposition of XRPD of compound 2HCl salt form A before and after heating to demonstrate stability.

FIG. 18 shows the TGA / DSC curve of compound 2 fumarate form A (812608-12-B).

FIG. 19 shows the 1H-NMR spectrum of compound 2 fumarate form A (812608-12-B), with limited EtOH residue detected (approximately 1.6%).

FIG. 20A shows the DVS plot of Compound 2 Free Base Form A (812608-05-A); FIG. 20B shows the overlay of XRPD of Compound 2 Free Base Form A before and after the DVS test; 20C shows the DVS plot of Compound 2 HCl Salt Form A (812608-12-A); FIG. 20D shows the overlay of XRPD of Compound 2 HCl Salt Form A before and after the DVS test; FIG. 20E shows a DVS plot of Compound 2 fumarate form A (812608-12-B); and FIG. 20F is a superposition of XRPD of Compound 2 fumarate form A before and after the DVS test. Is shown. FIG. 20A shows the DVS plot of Compound 2 Free Base Form A (812608-05-A); FIG. 20B shows the overlay of XRPD of Compound 2 Free Base Form A before and after the DVS test; 20C shows the DVS plot of Compound 2 HCl Salt Form A (812608-12-A); FIG. 20D shows the overlay of XRPD of Compound 2 HCl Salt Form A before and after the DVS test; FIG. 20E shows a DVS plot of Compound 2 fumarate form A (812608-12-B); and FIG. 20F is a superposition of XRPD of Compound 2 fumarate form A before and after the DVS test. Is shown. FIG. 20A shows the DVS plot of Compound 2 Free Base Form A (812608-05-A); FIG. 20B shows the overlay of XRPD of Compound 2 Free Base Form A before and after the DVS test; 20C shows the DVS plot of Compound 2 HCl Salt Form A (812608-12-A); FIG. 20D shows the overlay of XRPD of Compound 2 HCl Salt Form A before and after the DVS test; FIG. 20E shows a DVS plot of Compound 2 fumarate form A (812608-12-B); and FIG. 20F is a superposition of XRPD of Compound 2 fumarate form A before and after the DVS test. Is shown. FIG. 20A shows the DVS plot of Compound 2 Free Base Form A (812608-05-A); FIG. 20B shows the overlay of XRPD of Compound 2 Free Base Form A before and after the DVS test; 20C shows the DVS plot of Compound 2 HCl Salt Form A (812608-12-A); FIG. 20D shows the overlay of XRPD of Compound 2 HCl Salt Form A before and after the DVS test; FIG. 20E shows a DVS plot of Compound 2 fumarate form A (812608-12-B); and FIG. 20F is a superposition of XRPD of Compound 2 fumarate form A before and after the DVS test. Is shown. FIG. 20A shows the DVS plot of Compound 2 Free Base Form A (812608-05-A); FIG. 20B shows the overlay of XRPD of Compound 2 Free Base Form A before and after the DVS test; 20C shows the DVS plot of Compound 2 HCl Salt Form A (812608-12-A); FIG. 20D shows the overlay of XRPD of Compound 2 HCl Salt Form A before and after the DVS test; FIG. 20E shows a DVS plot of Compound 2 fumarate form A (812608-12-B); and FIG. 20F is a superposition of XRPD of Compound 2 fumarate form A before and after the DVS test. Is shown. FIG. 20A shows the DVS plot of Compound 2 Free Base Form A (812608-05-A); FIG. 20B shows the overlay of XRPD of Compound 2 Free Base Form A before and after the DVS test; 20C shows the DVS plot of Compound 2 HCl Salt Form A (812608-12-A); FIG. 20D shows the overlay of XRPD of Compound 2 HCl Salt Form A before and after the DVS test; FIG. 20E shows a DVS plot of Compound 2 fumarate form A (812608-12-B); and FIG. 20F is a superposition of XRPD of Compound 2 fumarate form A before and after the DVS test. Is shown.

FIG. 21 shows the kinetic solubility files of the two salts of Compound 2 and the free base at room temperature.

FIG. 22 shows the XRPD superposition of the samples before and after the stability test.

FIG. 23 shows the superposition of XRPD in the Compound 2 HCl salt form A sample.

FIG. 24 shows the TGA / DSC curve for compound 2 HCl salt form A (812608-16-A).

FIG. 25 shows the XRPD pattern of compound 2 HCl salt form C (812608-21-A2).

FIG. 26 shows the TGA / DSC curve for compound 2 HCl salt form C (812608-21-A2).

FIG. 27 shows the superposition of XRPD of compound 2 HCl salt form C (812608-27-B) before and after heating.

FIG. 28 shows the DSC superposition of compound 2 HCl salt form C (812608-27-B) before and after heating.

Figure 29 shows an overlay of XRPD of sample (812608-27-C) before and after heating, is heated to about 170 ° C. under _{N 2,} cooled to 30 ° C., was exposed to ambient conditions It is sometimes shown that a sample containing a mixture of HCl salt forms C + D is converted to a mixture of forms A + C.

Figure 30 shows an overlay of XRPD of sample (812608-27-D) before and after heating, is heated to about 140 ° C. under _{N 2,} cooled to 30 ° C., was exposed to ambient conditions It is sometimes shown that a sample containing a mixture of HCl salt forms C + E is converted to a mixture of forms A + C.

FIG. 31 shows the superposition of XRPD for compound 2 HCl salt form G (812608-21-A3_C). Shape change, HCl salt form C (812608-21-A3, obtained by evaporation from THF / _{H 2} O) is ambient conditions (21 ± 1.5 ℃, 60 ± 20% RH) is exposed to 6 days It is observed afterwards and is referred to as HCl salt form G.

32A, 32B, and 32C show charts comparing Compound 2 with known CNS agents as comparative factors. Scores of multiple parameters (“myMPO”) are incorporated into physicochemical properties to predict BBB penetration. The higher the score (5 is ideal), the better the chance of CNS penetration. 32A, 32B, and 32C show charts comparing Compound 2 with known CNS agents as comparative factors. Scores of multiple parameters (“myMPO”) are incorporated into physicochemical properties to predict BBB penetration. The higher the score (5 is ideal), the better the chance of CNS penetration. 32A, 32B, and 32C show charts comparing Compound 2 with known CNS agents as comparative factors. Scores of multiple parameters (“myMPO”) are incorporated into physicochemical properties to predict BBB penetration. The higher the score (5 is ideal), the better the chance of CNS penetration.

FIGS. 33A and 33B show the results of comparisons made between the powder capsule formulation and the liquid formulation of Compound 2, demonstrating the plasma concentration equivalent to that of the two formulations of a single species. FIGS. 33A and 33B show the results of comparisons made between the powder capsule formulation and the liquid formulation of Compound 2, demonstrating the plasma concentration equivalent to that of the two formulations of a single species.

Detailed Description of the Disclosure The present disclosure describes diseases (eg, cancer, eg, diffuse true pontine glioma (DIPG)) associated with abnormal ACVR1 expression (eg, mutations in the expressed protein) by administration of an ACVR1 inhibitor; It relates to a method of treating a genetic disorder (eg, progressive ossifying fibrodysplasia (FOP); etc.).

Prior to discussing this disclosure in more detail, it is believed that providing definitions of certain terms as used herein will aid in their understanding. Additional definitions are given throughout this disclosure.

"Amino" refers to _{two -NH groups.}

"Cyanide" or "nitrile" refers to the -CN group.

"Halo" refers to the -F, -Cl, -Br, or -I groups.

"Hydroxy" or "hydroxyl" refers to the -OH group.

"Imino" refers to the = NH substituent.

"Nitro" refers to _{two -NOs.}

"Oxo" refers to the = O substituent.

"Tioxo" refers to the = S substituent.

An "alkyl" is a linear or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms and is saturated or unsaturated (ie, one or more double (alkenyl) bonds. And / or containing a triple (alkynyl) bond), having 1 to 12 carbon atoms (C _{1 to} C ₁₂ alkyl), preferably 1 to 8 carbon atoms (C _{1 to} C ₈ alkyl) or A group that has 1 to 6 carbon atoms (C _{1 to} C ₆ alkyl) and is attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), 3-methylhexyl, 2-methylhexyl, ethenyl, propa-1-enyl, porcine-1-enyl, penta-1-enyl, There are penta-1,4-dienyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Alkyl containing one or more carbon-carbon double bonds are alkenyl. An alkyl containing one or more carbon-carbon triple bonds is an alkynyl. Unless otherwise specified herein, alkyl groups are substituted as needed.

"Alkoxy" refers to _{a group of formula-OR a, where Ra} is the above defined alkyl group containing 1 to 12 carbon atoms. Alkoxy groups are optionally substituted, unless otherwise indicated herein.

"Condensation" refers to any ring structure described herein that is fused to the existing ring structure of the ACVR1 inhibitor of the present disclosure. When the fused ring is a heterocyclyl ring, any carbon atom on the existing ring structure that becomes the portion between the condensed heterocyclyl ring or the condensed heteroaryl may be replaced with a nitrogen atom.

A "heterocyclyl" or "heterocyclic ring" is a stable 3 to 18 containing 2 to 12 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Refers to a member non-aromatic ring group. Unless otherwise specified herein, the heterocyclyl group may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system which may include a condensed or crosslinked ring system; in the heterocyclyl group. Nitrogen, carbon, or sulfur atoms may be oxidized as needed; nitrogen atoms may be quaternized as needed; heterocyclyl groups are partially saturated or fully saturated. obtain. Examples of such heterocyclyl groups include dioxolanyl, thienyl [1,3] dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isooxazolidinyl, morpholinyl, octahydroindolyl, octahydro. Isoindrill, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolydinyl, quinucridinyl, thiazolidinyl, tetrahydrofuryl, trithianil, tetrahydropyrani Includes le, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified herein, heterocyclyl groups may be optionally substituted.

As used herein, the term "substituted" means that at least one hydrogen atom is transferred to non-hydrogen radicals such as amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, and alkoxy. Means any of the above groups (eg, alkyl, alkoxy, and / or heterocyclyl) that have been replaced by the bonds of, and each of the above radicals is required by one or more of the above substituents. It may be substituted accordingly, and "substituted" means that one or more hydrogen atoms are NR _g R _h , NR _g C (= O) R _h , NR _g C (= O) NR _g R _h. , NR _g C (= O) OR _h , NR _g SO ₂ R _h , OC (= O) NR _g R _h , OR _g , SR _g , SOR _g , SO ₂ R _g , OSO ₂ R _g , SO ₂ OR _It also includes any of the above groups replaced by g, NSO ₂ R _g , or SO ₂ NR _g R _h. “Substituted” means that one or more hydrogen atoms are C (= O) R _g , C (= O) OR _g , C (= O) NR _g R _h , CH ₂ SO ₂ R _g , or It also means any of the above groups replaced by _{CH 2} SO ₂ NR _g R _h. In the above, R _g and R _h are the same or different, independently hydrogen, or optionally substituted alkyl.

The "prodrug" is intended to indicate an ACVR1 inhibitor that can be converted to the biologically active salts described herein under physiological conditions or by solvolysis. Thus, the term "prodrug" refers to a precursor of a pharmaceutically acceptable biologically active ACVR1 inhibitor. In some embodiments, the prodrug is inactive when administered to the subject, but is converted in vivo to an active ACVR1 inhibitor, for example by hydrolysis. Prodrug ACVR1 inhibitors often provide the benefits of solubility, histocompatibility, or delayed release in the subject organism (eg, Bundgard, H., Design of Prodrugs (1985), pp. 7-9, 21-24). (See Elsevier, Amsterdam). A discussion of prodrugs, both fully incorporated herein by reference, Higuchi, T., et al., "Pro drugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14, And Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The term "prodrug" is used when such a prodrug is administered to a subject. It is also intended to include any covalent carrier that releases the active ACVR1 inhibitor on the vivo. The active ACVR1 inhibitor prodrugs described herein are conventional operations on the parentally active ACVR1 inhibitor. Alternatively, it is typically prepared by modifying the functional groups present in the active ACVR1 inhibitor in such a way that the modification is cleaved either in vivo. The prodrug is an ACVR1 inhibitor. The hydroxy, amino, or mercapto group is cleaved when the active ACVR1 inhibitor prodrug is administered to the subject and is attached to any group that forms a free hydroxy, free amino, or free mercapto group, respectively. Examples of prodrugs include acetates, formates, and benzoate derivatives of hydroxy functional groups, such as active ACVR1 inhibitors, or acetamides, formamides, and benzamide derivatives of amine functional groups.

The present disclosure is an isotope-labeled all pharmaceutically acceptable ACVR1 inhibitor of formula (I) in which one or more atoms are replaced by atoms having different atomic masses or mass numbers. Is also intended to include. Examples of isotopes that can be incorporated into the disclosed ACVR1 inhibitors, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as each ^{2 H, 3 H, 11 C} , 13 Included are C, ¹⁴ C, ¹³ N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ³⁶ Cl, ¹²³ I, and ^{125 I.} These radiolabeled ACVR1 inhibitors help determine or measure the efficacy of ACVR1 inhibitors, for example by characterizing the binding affinity for the site or morphology of action, or pharmacologically important sites of action. Can be useful. Certain isotope-labeled ACVR1 inhibitors of formula (I) incorporating, for example, radioisotopes are useful for drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ^{3 H,} and ^carbon-14, i.e. ^{14 C,} from the viewpoint of ease and easy detection means of the incorporation, are particularly useful for this purpose.

Deuterium, i.e., substitution with heavier isotopes such as ^{2 H} may provide greater metabolic stability resulting certain therapeutic advantages, such as long since in vivo half-life or reduced dosing requirements It can and is therefore considered preferable in some situations.

Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O, and ¹³ N can be useful for positron emission tomography (PET) studies to test substrate receptor occupancy. Isotope-labeled ACVR1 inhibitors of formula (I) generally use suitable isotope-labeled reagents by conventional techniques known to those of skill in the art or in place of previously used non-labeled reagents. It can be prepared by a process similar to that described in the preparations and examples set forth in.

The disclosure is also intended to include in vivo metabolized products of the disclosed ACVR1 inhibitors. Such products can be obtained, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc. of administered ACVR1 inhibitors, primarily due to enzymatic processes. Accordingly, the present disclosure includes ACVR1 inhibitors produced by a process comprising administering to a subject the ACVR1 inhibitor of the present disclosure for a period sufficient to result in its metabolic products. Such products are typically identified by administering the radiolabeled ACVR1 inhibitor of the present disclosure to animals at detectable doses, such as to rats, mice, guinea pigs, monkeys, or humans. Sufficient time is available to generate metabolism, the conversion product of which is isolated from urine, blood, or other biological sample.

"Stable ACVR1 Inhibitors" and "Stable Structures" are ACVR1 inhibitors that are robust enough to survive after isolation from the reaction mixture to useful purity and formation into effective therapeutic agents. Is intended to indicate.

The use of the words "as needed" or "as needed" means that the event or situation described thereafter may or may not occur, and that description causes the event or situation. Means to include cases and cases where it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, the description of which is both a substituted aryl group and an unsubstituted aryl group. Means to include.

"Pharmaceutically acceptable salts" include both acid and base addition salts.

"Pharmaceutically acceptable acid addition salts" include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, Asparagic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, capricic acid, carbonic acid, silicate acid, citric acid, cyclamic acid, dodecyl sulfate, Ethan-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactalic acid, gentidic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutar Acids, glycerophosphates, glycolic acids, horse uric acid, isobutyl acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucilage, naphthalene-1,5-disulfonic acid, Naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotoic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvate, salicylic acid, 4-aminosalicylic acid, Refers to salts formed with organic acids such as sebacic acid, stearic acid, succinic acid, tartrate acid (eg L- (+)-tartrate acid), thiosian acid, p-toluenesulfonic acid, trifluoroacetic acid, and undecylene acid. ..

"Pharmaceutically acceptable base addition salt" refers to a salt prepared from the addition of an inorganic or organic base to a free acid. Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include primary, secondary, and tertiary amines, substituted amines containing naturally occurring substituted amines, cyclic amines, basic ion exchange resins such as ammonia, isopropylamine, etc. Trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, venetamine, Includes salts such as benzacine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

In some embodiments, pharmaceutically acceptable salts include quaternary ammonium salts, such as quaternary amine alkyl halide salts (eg, methyl bromide).

Often, crystallization produces a solvate of the ACVR1 inhibitors of the present disclosure. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the solvent as well as one or more molecules of the ACVR1 inhibitor of the present disclosure. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Thus, the ACVR1 inhibitors of the present disclosure include hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, and the like, as well as hydrates. It may exist as the corresponding solvated form. The ACVR1 inhibitor of the present disclosure may be a true solvate, while in other cases the ACVR1 inhibitor of the present disclosure may simply retain ancillary water or in water. It may be a mixture with some incidental solvent added.

The ACVR1 inhibitors of the present disclosure, or pharmaceutically acceptable salts or tautomers thereof, may contain one or more asymmetric centers and thus enantiomers, diastereomers, and other. There may be stereoisomers that can be defined as (R)-or (S)-or (D)-or (L)-with respect to amino acids from the point of view of absolute stereochemistry. The present disclosure is intended to include all such potential isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)-and (S)-, or (D)-and (L) -isomers can also be prepared using chiral synthons or chiral reagents. Well, or may be partitioned using conventional techniques such as chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or racemates (or salts or salts) using, for example, chiral high performance liquid chromatography (HPLC). Includes division of the racemic form of the derivative. If the ACVR1 inhibitors described herein contain olefin double bonds or other centers with geometric symmetry, unless otherwise indicated, the ACVR1 inhibitors are of E and Z geometric isomers. It is intended to include both. Similarly, all tautomers are intended to be included.

"Steroisomer" refers to an ACVR1 inhibitor having a different three-dimensional structure composed of the same atoms bonded by the same bond but not exchangeable. The present disclosure includes an "enantiomer" that refers to two stereoisomers that are mirror images of various stereoisomers and mixtures thereof, the molecules of which cannot be superimposed on each other.

The term "substantially" refers to a significant qualitative or quantitative range. As an example, when used in the context of referring to a particular characterization of a compound, the term identifies a chemical based on material similarity with a referenced characterization method such as XRPD, DSC, or TGA. Refers to the ability to do. The margin of error of such techniques is included in the term "substantially" as will be understood by those skilled in the art. Further, as used herein, "substantially pure", when used in terms of form, refers to 90, 91, 92, 93, 90, 91, 92, 93, of an ACVR1 inhibitor such as Compound 2, relative to the weight of the compound. 94, 95, 96, 97, 98, 98.5, 99, 99.1, 99.2, 99.3, 99.4, 99.5, 99.6, 99.7, 99.8, 99. It means a compound having a purity greater than 90% by weight, including a value greater than 9% by weight and also including a value equal to 100% by weight. The remaining material comprises other forms (s) of compounds resulting from its preparation and / or reaction impurities and / or processing impurities. For example, the crystalline form of compound 2 has a purity greater than 90% by weight when measured by means known and generally accepted in the art at this time, with less than 10% by weight remaining in the material. It may be considered substantially pure as it contains other forms (s) of compound 2 and / or reaction and / or processing impurities. Another way to define being substantially pure is as follows: as used herein, the term "substantially pure" when referring to a particular polymorphic form is: It means that the polymorphic form comprises any other physical form of the compound, less than 10% by weight, preferably less than 5% by weight, more preferably less than 3% by weight, most preferably less than 1% by weight.

"Tautomer" refers to a proton shift from one atom of a molecule to another atom of the same molecule, eg, a conversion from a ketone to an enol via a proton shift. The present disclosure includes tautomers of any said ACVR1 inhibitor.

A "pharmaceutical composition" refers to a formulation of one or more therapeutic agents and a medium generally accepted in the art for delivery of a biologically active agent to a subject, eg, a human. Such vehicles include all pharmaceutically acceptable carriers, diluents, or excipients. "Pharmaceutically acceptable carriers, diluents, or excipients" are any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / colorants, fragrance enhancers, surfactants. Activators, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that may be acceptable for use in humans or domesticated animals. Includes those approved by.

A "chemotherapeutic agent" or "antineocancer agent" is a chemical substance that destroys cancer cells or stops or slows the growth of cancer cells.

"Cancer," including "tumor," refers to the inhibition of uncontrolled growth and / or abnormally increased cell survival and / or apoptosis of cells that interferes with the normal functioning of body organs and systems. "Cancer" (eg, tumor) includes solid and non-solid cancers. A subject with cancer or tumor has an objectively measurable number of cancer cells present in the subject's body. "Cancer" includes benign and malignant cancers (eg, benign and malignant tumors, respectively), as well as latent or micrometastases.

"Metastasis" refers to the spread of cancer from its primary site to other parts of the body. "Metastasis" is a cancer that moves from its original location and is sown in vital organs, which can eventually lead to death due to functional deterioration of the affected organ. Metastasis is a sequential process that allows cancer cells to leave the primary tumor, invade lymph and blood vessels, circulate through the bloodstream, and grow in distal lesions in normal tissue elsewhere in the body. There is (transfers). At new sites, cells can establish a blood supply and grow to form life-threatening masses. Metastases can be local or distal. Both stimulatory and inhibitory molecular pathways within tumor cells regulate this behavior, and the interaction between tumor cells and host cells at new sites is also significant.

"Treatment" or "treatment," as used herein, refers to the application of medical or medical care to a subject of interest, such as a person with a disease or condition: (i). Inhibiting a disease or condition, i.e. stopping its onset; (ii) alleviating a disease or condition, i.e. retreating a disease or condition; or (iii) coping with an underlying disease or condition. Includes relieving symptoms (eg, pain, weight loss, coughing, fatigue, weakness, etc.) that result from a disease or condition without doing so. As used herein, the terms "disease" and "condition" may be used synonymously, or a particular disease or condition may not have a known pathogen (as used herein). Therefore, the pathogenesis has not yet been identified), and therefore a more or less specific set of symptoms has been identified by the clinician, not yet recognized as a disease but simply as an undesired condition or syndrome. In terms of points, they may differ.

"Subjects" include humans, domesticated animals such as laboratory animals (eg dogs, monkeys, rats, mice, etc.), domestic pets (eg, cats, dogs, rabbits, etc.), and livestock (eg, cats, dogs, rabbits, etc.). Includes pigs, cows, sheep, goats, horses, etc.), and untamed animals (eg, bears, elephants, yamaarashi, etc.). In embodiments, the subject is a mammal. In embodiments, the subject is a human. The term "patient" may be used synonymously with the term "subject".

FD & C Act defines a "child" as a subject 21 years or younger at the time of its diagnosis or treatment. The pediatric subpopulation further includes: (i) newborns-from birth to 28 days; (ii) infants-29 days to less than 2 years; (iii) children-2 years to less than 12 years; and (iv) adolescents- Characterized from 12 to 21 years old. Despite the definition, depending on the vulnerable patient population and clinical trial evaluation, the approved regulatory label contains the wording that it specifically modifies the scope of the pediatric population, for example pediatric patients up to 22 years of age. May be good.

An "effective amount" or "therapeutically effective amount" refers to an amount of an ACVR1 inhibitor or composition sufficient for effective treatment of a subject's cancer when administered to a subject such as a human. The amount of the ACVR1 inhibitor or composition constituting the "effective amount" is the amount of the ACVR1 inhibitor or composition, the condition to be treated and its severity, the method of administration, the duration of treatment, and / or the subject to be treated. Depending on age, one of ordinary skill in the art can make decisions as usual based on his or her knowledge and the present disclosure. In embodiments, the "effective amount" is treated as measured by statistically significant changes in one or more signs, symptoms, signs, diagnostic tests, and vital signs (eg,). Treat, prevent, inhibit, alleviate, promote, improve, increase, and reduce, etc.). In other embodiments, the "effective amount" suppresses the condition as measured by the lack of statistically significant changes in one or more signs, symptoms, signs, diagnostic tests, and vital signs, etc. And manage or prevent.

As used herein, "statistically significant" refers to a p-value of 0.050 or less as calculated using Student's t-test, a particular event or measured. Indicates that the results are unlikely to occur by chance.

In the description of the present invention, any concentration range, percentage range, ratio range, or integer range is any integer value within the listed range and, where appropriate, a fraction thereof, unless otherwise indicated. It is understood to include (such as one tenth and one hundredth of an integer). It is also understood that any numerical range listed herein with respect to any physical feature such as polymer subunit, size, or thickness also includes any integer within the listed range unless otherwise indicated. Will be done. As used herein, the term "about" means ± 20%, ± 10%, ± 5%, or ± 1% of the indicated range, value, or structure, unless otherwise indicated. do. As used herein, it should be understood that the terms "a" and "an" refer to "one or more" of the listed components. The use of alternatives (eg, "or") should be understood to mean one, both, or any combination thereof.

Unless the context requires otherwise, the term "comprise" and examples thereof, such as "comprises" and "comprising", and "include" throughout the specification and claims. Synonyms such as "include" and "have" and its variants are to be interpreted in an open and comprehensive sense; that is, "including but not limited to". The enumeration of items in the list, as interpreted, does not preclude other similar items that may also be useful in the materials, compositions, devices, and methods of the art. The open-ended term "comprising" as a synonym for terms such as include, contain, or have is used herein to describe and assert the disclosure, but the techniques of the invention. Alternatively, embodiments thereof may be described using the more restrictive term "consisting of" or "consisting of essentially" of the listed components.

Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

As used throughout the present specification as "one embodiment" or "embodiment," certain features, structures, or properties described in connection with an embodiment are included in at least one embodiment of the present disclosure. Means to be. Thus, the appearance of the words "in one embodiment" or "in an embodiment" at various locations throughout the specification does not all refer to the same embodiment. Similarly, the terms "can" and "may" and their variants are intended to be non-limiting and thus include certain elements or features of the embodiment. The citation that can or may include does not preclude other embodiments of the art of the invention that do not contain those elements or features. In addition, specific features, structures, or properties may be combined in any suitable manner in one or more embodiments.

In the following description, certain details are provided to provide a complete understanding of the various embodiments of the present disclosure. However, one of ordinary skill in the art will appreciate that this disclosure can be carried out without these details.
Pharmacology

Diffuse true pons glioma (DIPG) is a brain tumor found in a part of the brain stem called the brain pons. The pons controls essential physical functions such as heartbeat, breathing, swallowing, eye movements, eyesight, and equilibrium. Although much less frequently than histologically similar lesions that occur in adults, advanced glioma in children has a major need that has not yet been met in clinical neuro-oncology. Jones C et al., Paediatric and adult malignant glioma: close relatives or distant cousins ?, Nat Rev Clin Oncol. 2012 May 29; 9 (7), incorporated herein by reference with respect to such background teachings of DIPG. See: 400-13.

DIPG tumors are universally fatal, with a median overall survival of 9-12 months. DIPGs can be diffusely infiltrated and have lower grade histological areas inside, but are very indistinguishable from WHO grade IV polymorphic glioblastoma (GBM) in the cerebral cortex. Therefore, attempts to improve survival in these children have been unsuccessful. Surgical incisions of these tumors are not possible due to their anatomical site, and clinical trials based on promising goals from the adult GBM literature have shown no benefit. For example, Warren, Diffuse intrinsic pontine glioma: poised for progress, Front Oncol. 2012; 2: 205, and Taylor et al., ACVR1 mutations in DIPG: lessons learned from FOP, Cancer Res., 2014 Sep 1: 74 (17) See: 4565-4570 (each incorporated herein by reference with respect to such background teachings of DIPG).

As described, DIPG affects children almost without exception. According to the Michael Mosier Defeat DIPG Foundation, approximately 200-400 children in the United States are diagnosed with DIPG each year. These children are typically between the ages of 4 and 11. DIPG accounts for nearly 10-15% of all brain tumors in children.

DIPG is an invasive tumor that can interfere with physical function and deprives children of their motor skills, communication skills, and even their ability to eat and drink. As DIPG tumors begin to grow, they can put pressure on the nerves that control essential physical functions regulated by the brain pons. Children with DIPG can experience diplopia, reduced eye movements, facial weakness or asymmetry, and weakness in the arms and legs. You may also have problems with walking, emphasis, conversation, chewing, and swallowing. As the tumor progresses, it can also interfere with breathing and heartbeat, ultimately leading to the death of the child.

Buczkowiz et al. Demonstrated that clinically classical DIPGs have diverse histological spectra. Buczkowicz et al., Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications, Acta Neuropathol. 2014 Oct; 128 (4): 573- 81. doi: 10.1007 / s00401-014-1319-6. See Epub 2014 Jul 22. Thus, in context, DIPG may be characterized as a pontine tumor with a histological diagnosis of invasive glioma-grade II to IV. Primary tumors of the brainstem may be diagnosed based on clinical trials and on neuroimaging studies using magnetic resonance imaging (MRI). The presumptive diagnosis of DIPG may be based on classical imaging features in the absence of histological diagnosis. Increasingly, histological confirmation may be obtained for both entry into research studies and characterization of tumor molecules. New techniques with stereotactic needle biopsy may also make biopsy safer. A biopsy may be recommended for pontine tumors if the diagnosis is uncertain based on the findings of imaging. Thus, stellate tumors dominate the brainstem. WHO grade 1 tumors such as pilocytic astrocytoma and ganglioglioma have a favorable prognosis, occurring throughout the brainstem, including the midbrain, locally within the pons or at the cervical medulla oblongata junction. It is possible and they are often outwardly proliferative. Low-grade diffuse astrocytomas (WHO grade 2) that occur outside the pons at other brainstem sites tend to be tumors with a more favorable prognosis. DIPG is a diffuse astrocytoma ranging from diffuse astrocytoma (WHO grade 2) to glioblastoma (WHO grade 4) when biopsied at diagnosis. On postmortem assessment, DIPG is generally also undifferentiated astrocytoma (WHO grade 3) or glioblastoma (WHO grade 4) by morphological criteria, but WHO grade 2 regions may also be identified. Approximately 80% of DIPGs can be classified by WHO as diffuse midline gliomas, regardless of histological grade. All diffuse midline gliomas, H3 K27M-mutants, are WHO grade 4 regardless of histological grade, reflecting an inadequate prognosis in children with this diagnosis. For example, Ballester et al., Morphologic characteristics and immunohistochemical profile of diffuse intrinsic pontine gliomas. Am J Surg Pathol 37 (9): 1357-64, 2013, and Louis DN et al., The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 131 (6): 803-20, 2016 (with respect to the characterization and diagnosis of DIPG and related disorders, each incorporated herein by reference).

Taylor et al. Published a whole-genome sequence study that revealed a quarter of DIPG cases due to internal somatic mutations in ACVR1. This gene encodes the type I bone morphogenetic protein (BMP) receptor ALK2, the rest causing progressive ossifying fibrodysplasia (FOP), a congenital anomaly syndrome when mutated in germline. It is affected in the same way as the one, resulting in the conversion of soft tissue into bone. This unexpected link points towards the importance of developmental biological processes in tumorigenesis and provides extensive experience in mechanistic understanding and drug development finally gained by FOP researchers for pediatric neuromas. .. For example, Taylor et al., ACVR1 mutations in DIPG: lessons learned from FOP, Cancer Res., 2014 Sep 1: 74 (17): 4565-4570, which is incorporated herein by reference with respect to such background teachings. Please refer.

Bone morphogenetic protein (BMP) is a pleiotropic growth factor that plays an essential role in coordinating tissue mechanisms throughout various organs in the body. BMP ligands interact with bone morphogenetic protein receptors (BMPRs) belonging to the transforming growth factor beta (TGF-b) superfamily of serine / threonine kinase receptors (Ikushima, H. and K. Miyazono, Biology of Transforming Growth Factor-beta Signalin. Curr Pharm Biotechnol, 2011, which is incorporated herein by reference with respect to such background teachings). The ligand binds to the type II receptor and then is replenished with the type I receptor to form a heteromer complex. As a complex, type II receptors phosphorylate type I receptors, which become active and phosphorylate downstream signaling molecules. The downstream action of activating these receptors is primarily carried out by the SMAD family of proteins. SMAD becomes phosphorylated and transmits signals from the cell membrane to the nucleus where it functions as a transcription factor to regulate gene expression (Massague, J., J. Seoane, and D. Wotton, Smad transcription). factors. Genes Dev, 2005. 19 (23): p. 2783-810, which is incorporated herein by reference with respect to such background teachings).

In individuals with chronic diseases such as cancer and inflammation, BMP signaling is constitutively activated leading to anemia. This condition, commonly referred to as chronic disease anemia (ACD), is a debilitating symptom associated with cancer patients (Cullis, JO, Diagnosis and management of anaemia of chronic disease: current status. Br J Haematol, 2011. 154. (3): p. 289-300, which is incorporated herein by reference with respect to such background teachings). Chronic anemia in cancer patients leads to extreme weakness and fatigue, which leads to an inadequate quality of life for these individuals. In these patients, BMP signaling via two BMP type I receptors, ALK2 (also known as ACVR1 as described) and ALK3, induces liver expression of a peptide hormone called hepcidin (Steinbicker). , AU, et al., Perturbation of hepcidin expression by BMP type I receptor deletion induces iron overload in mice. Blood, 2011. 118 (15): p. 4224-30, which is referred to for such background teaching. Incorporated herein by.

Hepcidin reduces serum iron levels by promoting the degradation of the iron transporter, ferroportin, resulting in increased iron storage in macrophages and other cell types and hemoglobin and red blood cell (RBC) function. Because of this, iron cannot be used. Supplementing a patient's iron intake does not reverse ACD, as only the iron digested due to the activated BMP pathway and high serum hepcidin levels is stored. Currently, ACD in cancer is controlled by limiting the physical activity of the patient, and blood transfusions are used in the most severe cases. Inhibition of BMP signaling in these patients may provide a real difference in their quality of life and ultimately with respect to how they respond to treatment, radiation, or surgery. Steinbicker, AU, et al., Inhibition of bone morphogenetic protein signaling immunos anemia associated with inflammation. Blood, 2011. 117 (18): p. 4915-23; Coyne, DW, Hepcidin: clinical utility as a diagnostic tool and therapeutic target. Kidney Int, 2011. 80 (3): p. 240-4; Theurl, I., et al., Pharmacologic inhibition of hepcidin expression reverses anemia of chronic disease in rats. Blood, 2011 , These are incorporated herein by reference with respect to such background teachings).

As mentioned above, progressive ossifying fibrodysplasia (FOP) is an autosomal dominant disorder of skeletal malformations, resulting in sporadic germline mutations in ACVR1 resulting in 1.5 million live births. Disables ectopic ossification, which occurs in 1 out of births. Shore EM et al., A recurrent mutation in the BMP type I receptor ACVR1 causes inherited and sporadic fibrodysplasia ossificans progressiva, Nat Genet. 2006 May; 38 ( 5): See 525-7. FOP is a disorder in which muscle tissue and connective tissues such as tendons and ligaments are gradually replaced by bone (ossification) and bone is formed outside the skeleton (extraosseous or ectopic bone), which restrains movement. Is. This process is generally prominent in young children, starting at the neck and shoulders, progressing below the body and into the limbs. Extraosseous bone formation develops a loss of mobility as the joint becomes affected. The inability to open the mouth completely can make conversation and eating difficult. Over time, people with this disorder may experience malnutrition due to their dietary problems. Extraosseous formation around the thorax, which limits lung dilation, can also result in dyspnea. Any trauma to the muscles of an individual with FOP, such as a fall or invasive medical procedure, causes episodes of muscle swelling and inflammation (myositis), after which more rapid ossification can occur in the injured area. Recurrence can also be caused by viral illnesses such as influenza.

Five sites of the mutation newly described in DIPG are also found in cases of FOP, along with an additional five sites across the GS and kinase domains of the encoded ALK2 protein. Kaplan FS et al., Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I, incorporated herein by reference with respect to such background teachings of FOP and DIPG. See receptor ACVR1, Hum Mutat. 2009 Mar; 30 (3): 379-90.

Effective measures are needed to control both FOP and DIPG. Radiation is a traditional treatment for newly diagnosed DIPGs. Conventional limited area radiation provides a response in more than 90 percent of children with DIPG. These responses are short-lived, but on average last for about 6 to 9 months. Several studies have been conducted to increase the dose of radiation therapy, none of which improved survival. Surgery is ruled out in both conditions and therapeutic antibodies appear inappropriate as the activating mutations found in ALK2 / ACVR1 affect only the cytoplasmic portion of the receptor.

In certain embodiments, the methods of the present disclosure are useful for treating abnormal ACVR1 expression, including diffuse true pontine glioma (DIPG) and progressive ossifying fibrodysplasia (FOP).

Certain methods disclosed herein serve to select a regimen of treatment for the subject in need thereof. That is, the present disclosure provides a method for selecting a treatment regimen as well as a method for treating itself. Other embodiments provide methods for selecting a treatment regimen and for treating a subject's disease based on a subject having a given genetic profile. In various embodiments, the methods of the present disclosure further include obtaining a sample from a subject and determining a genetic profile.

The embodiments provided herein include methods for selecting treatment regimens for a subject based on the subject's genetic profile. Such gene profiles may be generated by any suitable technique (eg, microarray, reverse transcription polymerase chain reaction (RT-PCR), RNA / DNA sequencing, etc.).

In some embodiments, the gene profile comprises one or more mutations in the ACVR1 gene. The term "gene" can include not only coding sequences, but also regulatory regions such as promoters, enhancers, and termination regions. The term can further include all introns and other DNA sequences spliced from the mRNA transcript, along with variants obtained from alternative splice sites. The gene sequence encoding a particular protein can be a DNA or RNA that directs the expression of the particular protein. These nucleic acid sequences may be DNA strand sequences transcribed into RNA or RNA sequences translated into specific proteins. Nucleic acid sequences include both full-length nucleic acid sequences and non-full-length sequences derived from full-length proteins.

In various embodiments, the subject to be treated has one or more mutations in the ACVR1 gene. In embodiments, the subject has a predetermined genetic profile that includes such mutations (s). In some embodiments, one or more mutations in the ACVR1 gene include missense mutations, frameshift mutations, duplications (ie, copy number variation), splice site mutations, or combinations thereof.

In embodiments, one or more mutations are (P197F198) L, C509S, D185G, D185N, D433N, E38FS, F265S, G225D, G264S, G328E, G328R, G328V, G328W, G356D, G50C, H320Y, I. , K31E, K345Q, L196P, L251S, M34I, N100D, N481I, P115S, P455A, Q207E, Q278P, R201I, R206C, R206H, R258G, R258S, R307Q, R325A, R375C, R375P , S440G, S469C, S56L, T298S, V234M, V91M, W98R, or a combination thereof. In embodiments, one or more mutations in the ACVR1 gene include R206H, G328V, R258G, or a combination thereof. In certain embodiments, one or more mutations in the ACVR1 gene include R206H.

In some embodiments, one or more mutations in the ACVR1 gene include missense mutations. In some embodiments, missense mutations are C509S, D185N, D433N, F265S, G225D, H320Y, I323V, K31E, K345Q, M34I, N100D, N481I, P115S, P455A, Q278P, R206C, R401M, S130F, S226. , S41F, S440G, S469C, S56L, T298S, V234M, V91M, or W98R. In some embodiments, one or more mutations in the ACVR1 gene include frameshift mutations. In some embodiments, the frameshift mutation is E38fs. In some embodiments, one or more mutations in the ACVR1 gene include splice site mutations. In some embodiments, the splice site mutation is G264S.

As used herein, the abbreviation for mutation indicates (naturally occurring amino acid) (position of that amino acid) (and amino acid present in the mutant peptide). For example, P197L indicates that proline at position 197 is replaced by leucine. In another example, (P197F198) L indicates that proline at position 197 and phenylalanine at position 198 are collectively replaced by a single leucine.

Such mutations may be detected using any suitable method. In embodiments, mutations are detected by contacting a sample with a reagent (eg, an antibody or nucleic acid primer) to generate a complex of reagents and markers (s) and detecting the complex. Antibodies can be conjugated to solid supports suitable for diagnostic assays according to known techniques such as passive binding. Antibodies can be conjugated to cell surface antigens for diagnostic assays according to known techniques such as flow cytometry, including multicolor flow cytometry. Antibodies can be conjugated to detectable labels or groups, such as radioactive labels, enzyme labels, and fluorescent labels, according to known techniques.

In various embodiments, an effective amount of the ACVR1 inhibitor is administered to the subject. In embodiments, the ACVR1 inhibitor is administered for the treatment of cancer. A wide variety of cancers, including solid tumors and leukemias, are suitable for the methods disclosed herein. In embodiments, the cancer is a solid cancer. In some embodiments, the cancer is brain cancer. In some embodiments, the cancer is uterine, ovarian, or cervical cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, uterine cancer is endometrial cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is colon cancer.

In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises an advanced solid tumor. In some embodiments, the cancer comprises advanced metastases or advanced solid tumors. In embodiments, the cancer comprises a brain tumor or a uterine tumor. In embodiments, the cancer is a non-solid cancer. In various embodiments, the cancer is a pre-metastatic cancer. In various embodiments, the cancer is a metastatic cancer.

Types of cancer that can be treated in various embodiments include: brain cancer, uterine cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, rectal cancer, gastrointestinal cancer, hematopoietic or lymphoid cancer , Skin cancer, and bone cancer.

In some embodiments, the cancer is brain cancer (eg, brain stem glioma, cerebellar astrocytoma, ependymoma, medulloblastoma, primordial neuroblastoma, visual tract, and hypothalamic glioma). In various embodiments, the brain cancer is a brain tumor. In various embodiments, the brain cancer is a glioma (eg, brain stem, astrocytoma, visual tract, and hypothalamus). In some embodiments, the glioma is a high-grade glioma. In some embodiments, the brain cancer is a brain stem glioma. In some embodiments, the brain cancer is DIPG. In some embodiments, the cancer is a central nervous system cancer (eg, central nervous system lymphoma). In some embodiments, the cancer is a neuroblastoma.

In some embodiments, the cancer is uterine, ovarian, or cervical cancer. In some embodiments, the cancer is uterine cancer. In some embodiments, the uterine cancer is endometrial cancer. In some embodiments, the endometrial cancer is endometrial cancer. In embodiments, the cancer is ovarian cancer (eg, ovarian adenocarcinoma).

In some embodiments, the cancer is lung cancer (eg, non-small cell, small cell). In certain embodiments, lung cancer is small cell lung cancer. In some embodiments, the cancer is breast cancer.

In some embodiments, the cancer is gastrointestinal cancer. In some embodiments, the cancer is upper airway gastrointestinal cancer. In some embodiments, the cancer is colorectal cancer. In some embodiments, the cancer is rectal cancer.

In some embodiments, the cancer is urinary tract cancer. In some embodiments, the cancer is prostate cancer.

In some embodiments, the cancer is hematopoietic or lymphoid cancer. In various embodiments, the cancer is leukemia (eg, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, hairy cells, acute T-cell leukemia, etc.) or lymphoma (eg, AIDS). Related, Berkit, skin T-cell hodgkin, non-hodgkin, primary central nervous system).

In embodiments, the cancer is skin cancer. In various embodiments, the cancer is melanoma (eg, cutaneous melanoma). In some embodiments, the cancer is bone cancer. In some embodiments, the cancer is a bone tumor (eg, osteosarcoma, malignant fibrous histiocytoma).

An exemplary mutation associated with a particular type of cancer is shown in Table 1.

Effective amounts of ACVR1 inhibitors reduce the number of tumor cells, reduce the number of metastases, reduce tumor volume, induce cancer cell apoptosis, induce cancer cell death, cancer cells Induces radiosensitivity in, inhibits angiogenesis near cancer cells, inhibits cancer cell growth, inhibits tumor growth, prevents metastasis, reduces the number of metastases, prolongs life expectancy, It can extend the lifespan of a subject, reduce cancer-related pain, and / or reduce cancer recurrence or recurrence after treatment. In various embodiments, the effects of administering an ACVR1 inhibitor can be assessed by objective x-ray assessment.

In other embodiments, the disease is a genetic disorder. In some embodiments, the disease is FOP.

（式中：
Ｒ^１は、ＨまたはＣ_１〜Ｃ_６アルコキシであり；
Ｒ^２は、Ｃ_１〜Ｃ_６アルコキシまたはヘテロシクリルであり；
Ｒ^３は、ハロまたはＣ_１〜Ｃ_６アルコキシであり；および
Ｒ^４は、ＨまたはＣ_１〜Ｃ_６アルキルである）、
またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有する、ＡＣＶＲ１阻害剤である。 In embodiments, the methods of treatment described herein include administering to a subject an effective amount of an ACVR1 inhibitor. In various embodiments, the ACVR1 inhibitor is represented by the following formula (I):

(During the ceremony:
R ¹ is H or C _{1 to} C ₆ alkoxy;
R ² _is C 1 -C ₆ alkoxy or heterocyclyl;
R ³ is halo or C _{1 to} C ₆ alkoxy; and R ⁴ is H or C _{1 to} C ₆ alkyl),
Or an ACVR1 inhibitor having a stereoisomer thereof, a pharmaceutically acceptable salt, a tautomer, or a prodrug.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＲ^４は本明細書で定義される通りである）、
またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有する。 Thus, in embodiments, the methods of the present disclosure include administering a treatment regimen containing an ACVR1 inhibitor to a subject having a predetermined gene profile containing one or more mutations in the ACVR1 gene, comprising administering the ACVR1 inhibitor. The agent has the following formula (I):

(In the formula, R ¹ , R ² , R ³ , and R ⁴ are as defined herein),
Or it has a stereoisomer thereof, a pharmaceutically acceptable salt, a tautomer, or a prodrug.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＲ^４は本明細書で定義される通りである）、
またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有する。 In a further embodiment, the methods of the present disclosure include a method of treating diffuse true pontine glioma (DIPG) of a subject, the method comprising administering to the subject a treatment regimen comprising an ACVR1 inhibitor, ACVR1. Inhibitors have the following formula (I):

(In the formula, R ¹ , R ² , R ³ , and R ⁴ are as defined herein),
Or it has a stereoisomer thereof, a pharmaceutically acceptable salt, a tautomer, or a prodrug.

ACVR1 inhibitor (I), in certain embodiments, ^{R 1} is H.

In some embodiments of ACVR1 inhibitor (I), ^{R 1} is a _C 1 -C ₆ alkoxy. In some _embodiments, C 1 -C ₆ alkoxy is methoxy.

In the embodiment of ACVR1 inhibitor (I), ^{R 2} is a _C 1 -C ₆ alkoxy. In certain _embodiments, C 1 -C ₆ alkoxy is methoxy.

In another embodiment of ACVR1 inhibitor (I), ^{R 2} is heterocyclyl. In certain embodiments, the heterocyclyl is a optionally substituted piperazinyl. In certain embodiments, piperazinyl optionally substituted _is a C 1 -C ₆ alkyl or _C 1 -C ₆ hydroxyalkyl.

In some embodiments of ACVR1 inhibitor (I), ^{R 3} is a halo. In certain embodiments, the halo is chloro.

In a further embodiment of the ACVR1 inhibitor (I), ^{R 3} is a _C 1 -C ₆ alkoxy. In certain embodiments, the C _1- C ₆ alkoxy is methoxy.

In the embodiment of ACVR1 inhibitor (I), ^{R 4} is a H. In some embodiments, ^{R 4} is _C 1 -C ₆ alkyl. In certain _embodiments, C 1 -C ₆ alkyl is methyl.

ＩＣ_５０（単位 ｎＭ）、ここで、＋＋は１，０００ｎＭから１０ｎＭであり；かつ＋＋＋は１０ｎＭ未満である。 In other, certain embodiments, the ACVR1 inhibitor is selected from the ACVR1 inhibitors in Table 2.

IC ₅₀ (unit: nM), where ++ is from 1,000 nM to 10 nM; and +++ is less than 10 nM.

またはその薬学的に許容される塩もしくはプロドラッグである。表２に関して参照を容易にするために、特定の実施形態では、ＡＣＶＲ１阻害剤は、式（２）の化合物またはその薬学的に許容される塩である。 In certain embodiments, the ACVR1 inhibitor is

Or its pharmaceutically acceptable salt or prodrug. To facilitate reference with respect to Table 2, in certain embodiments, the ACVR1 inhibitor is a compound of formula (2) or a pharmaceutically acceptable salt thereof.

またはその薬学的に許容される塩もしくはプロドラッグである。 In certain embodiments, the ACVR1 inhibitor is

Or its pharmaceutically acceptable salt or prodrug.

またはその薬学的に許容される塩もしくはプロドラッグである。 In certain embodiments, the ACVR1 inhibitor is

Or its pharmaceutically acceptable salt or prodrug.

またはその薬学的に許容される塩もしくはプロドラッグである。 In certain embodiments, the ACVR1 inhibitor is

Or its pharmaceutically acceptable salt or prodrug.

またはその薬学的に許容される塩もしくはプロドラッグである。 In certain embodiments, the ACVR1 inhibitor is

Or its pharmaceutically acceptable salt or prodrug.

またはその薬学的に許容される塩もしくはプロドラッグである。 In certain embodiments, the ACVR1 inhibitor is

Or its pharmaceutically acceptable salt or prodrug.

In various embodiments, the pharmaceutically acceptable salt is an acid addition salt. In some embodiments, the acid addition salt is a hydrochloride salt.

Any embodiments, and wherein in ACVR1 inhibitor (I) above, particular substituents described herein in ACVR1 inhibitors of above formula (I) ^(e.g., R 1 ^{to R} 4) Any of these can be independently combined with other embodiments and / or substituents of the ACVR1 inhibitor of formula (I) to form embodiments of the present disclosure not specifically mentioned above. Understood. In addition, in events where the list of substituents is listed for any particular R group in a particular embodiment and / or claim, each individual substituent is deleted from the particular embodiment and / or claim. It is understood that the remaining list of substituents may be considered to be within the scope of the present disclosure. In this description, it is understood that the substituent and / or variable combinations of the formulas shown are only acceptable if such contributions result in a stable ACVR1 inhibitor.

The ACVR1 inhibitors of the present disclosure can be prepared according to any number of methods known in the art, including those described in US 2016/0214944, which are incorporated herein by reference.

All ACVR1 inhibitors presently present in free base or acid form shall be converted to their pharmaceutically acceptable salts by treatment with appropriate inorganic or organic bases by methods known to those of skill in the art. Can be done. The salts of ACVR1 inhibitors of the present disclosure can be converted to their free base or acid form by standard techniques.

The ACVR1 inhibitors described herein (ie, the ACVR1 inhibitors of formula (I)) can be used in combination with one or more other additional therapeutic agents. The dosage of the ACVR1 inhibitor can be adjusted for any drug-drug response.

（式中、Ｒ^１、Ｒ^２、Ｒ^３、およびＲ^４は、本明細書で定義される通りである）
またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有する。 Thus, in embodiments, the methods of the present disclosure include treating a solid tumor, DIPG, or FOP of interest, the method comprising administering to the subject a treatment regimen, wherein the treatment regimen is an ACVR1 inhibitor and. ACVR1 inhibitors, including additional therapeutic agents, have the following formula (I):

(In the formula, R ¹ , R ² , R ³ , and R ⁴ are as defined herein).
Or it has a stereoisomer thereof, a pharmaceutically acceptable salt, a tautomer, or a prodrug.

In various embodiments, the additional therapeutic agent is a retinoic acid receptor gamma agonist; mTOR inhibitor; activin A antibody; kinase inhibitor; ACVR1 antibody; TAK1 inhibitor; phosphodiesterase inhibitor; HDAC inhibitor; chemotherapeutic agent; Immunotherapeutic agents; Cell therapy; Peptide or tumor lysate vaccines; Irinotecan; TTRNA-DC vaccine with GM-CSF, TTRNA-xALT; Integrin inhibitors; IL-12 therapy; Anti-neoplastone therapy; Imikimod; Tumor-dissolving adenovirus WEE1 inhibitors; WT1 protein-derived peptide vaccines; pegged interferon alpha 2b; kinase antibodies; smoothing inhibitors; tubulin inhibitors; telomerase inhibitors; CD40 agonists; GM-CSF agonists; IDO inhibitors; and radioiodine labeling Includes one or more of the monoclonal antibodies 8H9.64.

In embodiments, the additional therapeutic agent comprises one or more of a retinoic acid receptor gamma agonist; an mTOR inhibitor; an activin A antibody; a kinase inhibitor; an ACVR1 antibody; a TAK1 inhibitor; and a phosphodiesterase inhibitor. In some embodiments, additional therapeutic agents are HDAC inhibitors; chemotherapeutic agents; immunotherapeutic agents; cell therapy; peptide or tumor lysate vaccines; irinotecan; TTRNA-DC vaccines with GM-CSF, TTRNA-xALT; Integrin inhibitor; IL-12 therapy; anti-neoplastone therapy; imikimod; tumor-soluble adenovirus; WEE1 inhibitor; WT1 protein-derived peptide vaccine; pegged interferon alpha 2b; kinase antibody; kinase inhibitor; smoothing inhibitor; It comprises one or more of a tubulin inhibitor; a telomerase inhibitor; a CD40 agonist; a GM-CSF agonist; an IDO inhibitor; and a radioactive iodine-labeled monoclonal antibody 8H9.

In embodiments, the kinase inhibitor inhibits a cyclin-dependent kinase (CDK). In some embodiments, the CDK is CDK9 or CDK7. In some embodiments, the CDK is CDK9. In various embodiments, the CDK9 inhibitor is siRNA, alvocidib, or a prodrug thereof, dynasicrib, or a combination thereof. In certain embodiments, the CDK9 inhibitor is arbocidim, or a prodrug thereof. Examples of such prodrugs (eg, phosphate prodrugs) are described in US Pat. No. 9,758,539, which is incorporated herein by reference. In embodiments, the kinase inhibitor inhibits phosphoinositide 3-kinase (PI3K).

In various embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In certain embodiments, the PD-1 inhibitor is pembrolizumab, nivolumab, or a combination thereof. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In certain embodiments, the PD-L1 inhibitor is atezolizumab, avelumab, durvalumab, or a combination thereof.

In some embodiments, the kinase antibody comprises a drug conjugate.

In certain embodiments, the retinoic acid receptor gamma agonist is parovarotene. In certain embodiments, the mTOR inhibitor is rapamycin or everolimus. In certain embodiments, the activin A antibody is REGN2447. In certain embodiments, the kinase inhibitors are salacatinib, momerotinib, dolsomorphin, imatinib, crizotinib, dasatinib, bevacizumab, erlotinib, vandetanib, ribociclib, clenoranib, abemaciclib, ONC201, sirengitide, albocitide, syrengitide, albocytide. In certain embodiments, the phosphodiesterase inhibitor is dipyridamol. In certain embodiments, the HDAC inhibitor is SAHA, vorinostat, or panobinostat. In certain embodiments, the immunotherapeutic agent is MDV9300. In certain embodiments, cell therapy comprises autologous dendritic cells. In certain embodiments, the peptide or tumor lysate vaccine comprises a K27M peptide or lindpepimut. In certain embodiments, irinotecan is administered by convection enhanced delivery. In certain embodiments, the integrin inhibitor is sirengitide. In certain embodiments, the anti-neoplaston therapy is attengenal or astugenal. In certain embodiments, the oncolytic adenovirus is DNX-2401. In certain embodiments, the WEE1 inhibitor is AZD1775. In certain embodiments, the WT1 protein-derived peptide vaccine is DSP-7888. In certain embodiments, the kinase antibody is nimotuzumab, erbitux, or ABT-414. In certain embodiments, the smoothing inhibitor is vismodegib. In certain embodiments, the tubulin inhibitor is mebendazole. In certain embodiments, the telomerase inhibitor is imeterstat. In certain embodiments, the CD40 agonist is APX005M. In certain embodiments, the GM-CSF agonist is salgramostin with a reoviridae. In certain embodiments, the IDO inhibitor is indoxymod.

In one embodiment, the additional therapeutic agent is a chemotherapeutic agent. In certain embodiments, the chemotherapeutic agent is melphalan, gemcitabine, temozolomide, cyclophosphamide, fludarabine, doxorubicin, irinotecan, renalidemid, valproic acid, chloroquin, carboplatin, etoposide, ifosfamide, pomalidemid, or lomustine.

The method can also be performed in combination with radiation therapy, and the amount of ACVR1 inhibitor combined with radiation therapy is effective in treating the disease.

In one embodiment, the radiation is provided prior to treatment with the compound of formula (I). In one embodiment, the radiation is provided after treatment with the compound of formula (I). In one embodiment, the radiation is provided both before and after treatment with the compound of formula (I). In one embodiment, treatment with the compound of formula (I) can re-irradiate the subject after a long period of time, reducing the side effects associated with radiation therapy.

Techniques for administering radiation therapy are known in the art and these techniques can be used in the combination therapies described herein. Administration of the ACVR1 inhibitors of the present disclosure in this combination therapy can be determined as described herein.

In some embodiments, the treatment regimen described herein further comprises surgical resection. Such techniques are known in the art.

In various embodiments, the subject is undergoing pretreatment for these diseases. In such embodiments, the subject may be refractory to the pretreatment or intolerant to the pretreatment. As used herein, "refractory" refers to a subject with progressive disease by RECIST, as described in Eur J Cancer. 2016 Jul; 62: 132-7, which is incorporated herein by reference. Indicates to represent. A subject is considered to have "progressive disease" based on RECIST if there is an increase of at least 20% in the target lesion, as will be appreciated by those skilled in the art. "Complete response" for DIPG refers to the disappearance of all target lesions. DIPG "partial response" refers to a reduction of at least 30% of the total target lesions, and "stable disease" does not contract sufficiently to suit PR or increase sufficiently to suit PD. As used herein, "intolerance" means that a subject is unable or unwilling to tolerate the adverse effects of an effective amount of therapeutic agent. In some embodiments, the subject is intolerant of the pretreatment regimen.

Efficacy for treatment with compounds of formula (I), especially with respect to DIPG, may be measured based on overall survival (OS) or progression-free survival (PFS), which can be calculated on a weekly, monthly, or yearly basis. .. In one embodiment, treatment with a compound of formula (I) is 6 months or longer, 9 months or longer, 1 year or longer, or 5 years or longer OS. I will provide a. In one embodiment, treatment with a compound of formula (I) provides at least 6 months, at least 9 months, at least 1 year, or at least 5 years of PFS.

In embodiments, the subject being treated has one or more markers at a predetermined level. In some embodiments, one or more markers are for regulating iron. In some embodiments, one or more markers are hepcidin levels, tumor loading, transferrin saturation, c-reactive protein (CRP), cardiac markers (type B sodium diuretic peptide (BNP), N-terminal). Includes proB-type sodium diuretic peptide (NT-proBNP)), serum iron, total iron, ferritin, transferrin, soluble transferrin receptor (STR), total iron binding capacity (TIBC), phospho-SMAD, or a combination thereof. In some embodiments, one or more markers are assessed using iron panels (ie, serum iron, ferritin, transferrin, STR, and TIBC). In various embodiments, one or more markers are in the phosphosignal transduction pathway downstream of ACVR1. In a further embodiment, one or more markers are gene expression markers downstream of ACVR1 / SMAD signaling.

In various embodiments, the subject to be treated has a level of a predetermined marker (eg, hepcidin) above the threshold.

Baseline levels can be derived from the population. A "population" is any grouping of objects or samples with similar specified characteristics. Grouping follows, for example, clinical parameters, clinical assessments, treatment regimens, disease states, severity of conditions, and the like.

In some embodiments, the population is randomly selected. In some embodiments, the population is a group comprising about 2, about 5, about 10, about 25, about 50, about 75, or about 100 subjects. In some embodiments, the population is about 200, about 300, about 500, about 1,000, about 1,500, about 2,000, about 3,000, about 5,000, or about 10,000. It is a group including the target of. In some embodiments, the population is a group containing less than about 10,000 subjects. In other embodiments, the population is a group containing more than about 10,000 subjects.

In some embodiments, the population includes individuals with and without cancer. In some embodiments, a portion of the population has solid cancer. In some embodiments, a portion of the population has brain cancer. In some embodiments, part of the population has uterine cancer.

In some embodiments, the population is a cancer-free group. In some embodiments, the population does not have solid cancer. In some embodiments, the population does not have brain cancer. In some embodiments, the population does not have uterine cancer.

In some embodiments, the population is a group with cancer. In embodiments, the population has solid cancers. In some embodiments, the population has brain cancer. In some embodiments, the population has uterine cancer. In some embodiments, the population has the same type of cancer as the subject.

In embodiments, the expression level of the marker (eg, hepcidin) is at least about 10% higher than the baseline expression level. In some embodiments, expression levels are at least about 1% greater, at least about 2% greater, at least about 3% greater, at least about 4% greater, at least about 5% greater, at least about 7% greater, at least about 12 % Large, at least about 15% larger, at least about 17% larger, at least about 20% larger, at least about 22% larger, at least about 25% larger, at least about 27% larger, at least about 30% larger, at least about 32% larger , At least about 35% larger, at least about 37% larger, at least about 40% larger, at least about 45% larger, at least about 50% larger, at least about 75% larger, or at least about 90% larger. In certain embodiments, the marker (eg, hepcidin) is upregulated. "Up-regulated" or "up-regulated" refers to increased presence of a protein and / or increased expression of its gene.

In some embodiments, the expression level of the marker (eg, hepcidin) is below the baseline expression level. In embodiments, marker expression levels are at least 10% less than baseline expression levels. In some embodiments, expression levels are at least about 1% less, at least about 2% less, at least about 3% less, at least about 4% less, at least about 5% less, at least about 10% less, at least about 12. % Less, at least about 15% less, at least about 17% less, at least about 20% less, at least about 22% less, at least about 25% less, at least about 27% less, at least about 30% less, at least about 32% less , At least about 35% less, at least about 37% less, at least about 40% less, at least about 45% less, at least about 50% less, at least about 75% less, or at least about 90% less. In certain embodiments, the marker (eg, hepcidin) is down-regulated. "Down-regulated" or "down-regulated" refers to a decrease in the presence of a protein and / or a decrease in the expression of its gene.

Measurement of the expression of a marker (eg, hepcidin) can be determined at the protein or nucleic acid level using any method known in the art. In some embodiments, marker expression involves contacting the sample with a reagent (eg, an antibody or nucleic acid primer) to generate a complex of the reagent with the marker (s) and detecting the complex. Detected. Antibodies can be conjugated to solid supports for diagnostic assays by known techniques such as passive binding. Antibodies can be conjugated to cell surface antigens for diagnostic assays according to known techniques such as flow cytometry, including multicolor flow cytometry. Antibodies can be conjugated to detectable labels or groups such as radioactive labels, enzyme labels, and fluorescent labels by known techniques.

Examples of suitable immunoassays include immunoblotting, immunoprecipitation, immunofluorescence, chemiluminescence, electrochemical luminescence (ECL), and ELISA. Up or down regulation of markers includes, for example, cDNA arrays, clone hybridization, differential display, differential screening, FRET detection, liquid microarrays, PCR, RT-PCR, Sanger sequencing, large-scale parallel (next generation) sequencing, molecular beacons. , Microelectric arrays, oligonucleotide arrays, polynucleotide arrays, continuous analysis of gene expression (SAGE), and / or subtractive hybridization can also be used for detection.

Expression can be determined in a sample collected from the subject prior to treatment. In such embodiments, expression levels may be used to predict responsiveness to a particular treatment. In some embodiments, the expression level may be used, at least in part, to determine the treatment administered to the subject. In some embodiments, the sample is collected approximately 28 days before the treatment regimen is administered. In some embodiments, the sample is collected approximately 14 days before the treatment regimen is administered. In some embodiments, the sample is collected approximately 7 days before the treatment regimen is administered. In some embodiments, the sample is collected approximately 72 hours before the treatment regimen is administered. In some embodiments, the sample is collected up to about 6 hours before the treatment regimen is administered.

In certain embodiments, the sample is dosed on day 1 of the first cycle of treatment, before dosing, 0.5 hours after dosing, 2 hours after dosing, 4 hours after dosing, 6 hours after dosing. 8 hours after dosing, 12 hours after dosing, and / or 24 hours after dosing. In certain embodiments, the sample is prepared on day 1 of the first cycle of treatment, before dosing, 0.5 hours after dosing, 2 hours after dosing, 4 hours after dosing, 6 hours after dosing, and. / Or collected 24 hours after dosing. In certain embodiments, samples are collected on day 1 of the first cycle of treatment, before dosing, 2 hours after dosing, 6 hours after dosing, and / or 24 hours after dosing. In some embodiments, the sample may be collected after a certain dose of treatment has been administered to the subject. In another particular embodiment, the sample is also collected on the 8th day of the first cycle of treatment, even before dosing. In some embodiments, the sample is collected prior to dosing on one or more of days 1, 7, 14, 21, and 28 of the first cycle of treatment. In certain embodiments, the sample is administered on day 21 of the first cycle of treatment, before dosing, 0.5 hours after dosing, 2 hours after dosing, 4 hours after dosing, 6 hours after dosing. 8 hours after dosing, 12 hours after dosing, and / or 24 hours after dosing. In certain embodiments, the sample is prepared on day 21 of the first cycle of treatment, before dosing, 0.5 hours after dosing, 2 hours after dosing, 4 hours after dosing, 6 hours after dosing, and. / Or collected 24 hours after dosing. In certain embodiments, samples are collected on the 21st day of the first cycle of treatment, 2 hours, and 6 hours before dosing. In certain embodiments, samples are collected on day 21 of the first cycle of treatment, before dosing, 2 hours after dosing, 6 hours after dosing, and / or 48 hours after dosing. In certain embodiments, samples are collected on days 8, 21, and 23 of the treatment cycle.

In another particular embodiment, the sample is also collected on the first day of the second cycle of treatment, before dosing. In some embodiments, the sample is collected up to 7 days before the first day of the second cycle. In another particular embodiment, the sample is also collected on the first day of the second cycle of treatment, 4 hours after treatment. In some embodiments, the sample is collected prior to dosing on one or more of days 1, 7, 14, 21, and 28 of the second cycle of treatment. In some embodiments, the sample is collected on one or more of days 1, 8, 15, 22, and 29 of the second cycle of treatment. In some embodiments, the sample is collected on the 21st day of the second cycle of treatment, prior to dosing. In a further specific embodiment, the sample is collected on the first day of any additional cycle of treatment (eg, third, fourth, fifth, etc.), prior to dosing. In some specific embodiments, the sample follows one of the schedules described herein prior to dosing over any additional cycle of treatment (eg, third, fourth, fifth, etc.). Collected. In another particular embodiment, the sample is also collected after the treatment is complete. In such embodiments, the sample may be collected within 14 days of the end of the procedure.

As will be appreciated, the type of sample collected will be selected based on the markers being tested. Any suitable sample (eg, plasma, serum, peripheral blood mononuclear cells (PBMC), etc.) can be used.

Up or down adjustments can be assessed by comparing the value with the relevant reference level. For example, the amount of one or more markers can be shown as a value that can be derived, for example, by measuring the level (s) of the markers (s) in the sample by the assay performed. can. In embodiments, the system and method provide quantitative detection of the presence of markers in the sample being assayed, i.e. the actual amount or relative presence of markers in the sample being assayed. A quantity is evaluated or rated. In such embodiments, the quantitative detection may be absolute, or relative if the method is a method of detecting two or more different markers in a sample. You may. Thus, the term "quantitate" can refer to absolute or relative quantification when used in the context of quantifying markers in a sample. Absolute quantification includes, for example, by including known concentrations (s) of one or more control markers and by referring to the detected levels of the markers with known control markers, eg by standardization. It can be achieved (eg, through the creation of standard curves). Alternatively, the relative quantification is the level or amount detected between the two or more different markers so that the relative quantification of each of the two or more markers is provided. This can be achieved, for example, by comparing with each other.

In various embodiments, the level of one or more markers is monitored after administration of the ACVR1 inhibitor.

In embodiments, the relationship between administration of the ACVR1 inhibitor and one or more markers may be quantified using Spearman's rank correlation statistics.

In some embodiments, one or more markers include hepcidin. In some embodiments, the subject is at least about 0.1 ng / mL, about 0.2 ng / mL, about 0.3 ng / mL, about 0.4 ng / mL, about 0.5 ng / mL, about 0. 6 ng / mL, about 0.7 ng / mL, about 0.8 ng / mL, about 0.9 ng / mL, about 1 ng / mL, about 1.5 ng / mL, about 2 ng / mL, about 2.5 ng / mL, about 3 ng / mL, about 4 ng / mL, about 5 ng / mL, about 6 ng / mL, about 7 ng / mL, about 8 ng / mL, about 9 ng / mL, about 10 ng / mL, about 12.5 ng / mL, about 15 ng / mL , About 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL , About 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL about 110 ng / mL, about 115 ng / mL, About 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, about 140 ng / mL, about 145 ng / mL, about 150 ng / mL, about 155 ng / mL, about 160 ng / mL, about 165 ng / mL, It has a predetermined hepcidin level of about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, about 190 ng / mL, about 195 ng / mL, or about 200 ng / mL.

In various embodiments, the subject is about 0.1 ng / mL to about 5 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL. , About 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL , About 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL, about 110 ng / mL, about 115 ng / mL, about 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, About 140 ng / mL, about 145 ng / mL, about 150 ng / mL, about 155 ng / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, It has a predetermined hepcidin level of about 190 ng / mL, about 195 ng / mL, or 200 ng / mL.

In various embodiments, the subject is about 0.5 ng / mL to about 5 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL. , About 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL , About 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL, about 110 ng / mL, about 115 ng / mL, about 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, About 140 ng / mL, about 145 ng / mL, about 150 ng / mL, about 155 ng / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, It has a predetermined hepcidin level of about 190 ng / mL, about 195 ng / mL, or about 200 ng / mL.

In various embodiments, the subject is about 1 ng / mL to about 5 ng / mL, about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about. 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL, about 110 ng / mL, about 115 ng / mL, about 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, about 140 ng / ML, about 145 ng / mL, about 150 ng / mL, about 155 ng / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, about 190 ng It has a predetermined hepcidin level of / mL, about 195 ng / mL, or about 200 ng / mL.

In various embodiments, the subject is about 5 ng / mL to about 10 ng / mL, about 15 ng / mL, about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about. 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL about 110 ng / mL, about 115 ng / mL, about 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, about 140 ng / mL, about 145 ng / ML, about 150 ng / mL, about 155 ng / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, about 190 ng / mL, about 195 ng It has a predetermined hepcidin level of / mL, or about 200 ng / mL.

In various embodiments, the subject is about 10 ng / mL to about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about. 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL about 110 ng / mL, about 115 ng / mL, about 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, about 140 ng / mL, about 145 ng / mL, about 150 ng / mL, about 155 ng Prescription of / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, about 190 ng / mL, about 195 ng / mL, or about 200 ng / mL Has hepcidin levels of.

In various embodiments, the subject is about 12.5 ng / mL to about 20 ng / mL, about 25 ng / mL, about 30 ng / mL, about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL. , About 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL , About 105 ng / mL about 110 ng / mL, about 115 ng / mL, about 120 ng / mL, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, about 140 ng / mL, about 145 ng / mL, about 150 ng / mL, About 155 ng / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, about 190 ng / mL, about 195 ng / mL, or about 200 ng / mL Has a given hepcidin level of.

In various embodiments, the subject is about 25 ng / mL to about 35 ng / mL, about 40 ng / mL, about 45 ng / mL, about 50 ng / mL, about 55 ng / mL, about 60 ng / mL, about 65 ng / mL, about. 70 ng / mL, about 75 ng / mL, about 80 ng / mL, about 85 ng / mL, about 90 ng / mL, about 95 ng / mL, about 100 ng / mL, about 105 ng / mL, about 110 ng / mL, about 115 ng / mL, about 120 ng / ML, about 125 ng / mL, about 130 ng / mL, about 135 ng / mL, about 140 ng / mL, about 145 ng / mL, about 150 ng / mL, about 155 ng / mL, about 160 ng / mL, about 165 ng / mL, about 170 ng It has a given hepsidin level of / mL, about 175 ng / mL, about 180 ng / mL, about 185 ng / mL, about 190 ng / mL, about 195 ng / mL, or about 200 ng / mL.

Hepcidin levels may be measured in molar concentrations. In some embodiments, the predetermined hepcidin level is at least 4 nM. In some such embodiments, the subject is a female. In some embodiments, the predetermined hepcidin level is at least 4.1 nM. In some such embodiments, the subject is a female. In some embodiments, the predetermined hepcidin level is at least 8.5 nM. In some such embodiments, the subject is a female. In some embodiments, the predetermined hepcidin level is at least 7.5 nM. In some such embodiments, the subject is a male. In some embodiments, the predetermined hepcidin level is at least 7.8 nM. In some such embodiments, the subject is a male.

In various embodiments, hepcidin levels are monitored after administration of the ACVR1 inhibitor.

In various embodiments, the subject has a given transferrin saturation below the threshold. "Transferrin saturation" refers to the value of serum iron divided by the total iron binding volume and can be determined using any technique known in the art.

In embodiments, the subject has less than about 50% transferrin saturation. In some such embodiments, the subject is a male. In embodiments, the subject has less than about 45% transferrin saturation. In some such embodiments, the subject is a female. In some embodiments, the subject has less than about 40% transferrin saturation. In some embodiments, the subject has transferrin saturation of less than about 35%. In some embodiments, the subject has less than about 30% transferrin saturation. In some embodiments, the subject has transferrin saturation of less than about 25%. In some embodiments, the subject has less than about 20% transferrin saturation. In some embodiments, the subject has transferrin saturation of less than about 15%. In some such embodiments, the subject is a female.

In some embodiments, the subject has transferrin saturation ranging from about 12% to about 50%. In some embodiments, the subject has transferrin saturation ranging from about 15% to about 50%. In some such embodiments, the subject is a male. In some embodiments, the subject has transferrin saturation ranging from about 12% to about 45%. In some such embodiments, the subject is a female. In some embodiments, the subject has transferrin saturation ranging from about 20% to about 40%. In some embodiments, the subject has transferrin saturation ranging from about 30% to about 45%. In some embodiments, the subject has transferrin saturation ranging from about 25% to about 35%. In some embodiments, the subject has transferrin saturation ranging from about 15% to about 25%. In some embodiments, the subject has transferrin saturation ranging from about 20% to about 30%.

In various embodiments, transferrin saturation levels are monitored after administration of the ACVR1 inhibitor.

In various embodiments, the subject has acceptable liver function. In such embodiments, the subject's bilirubin is ≤1.5 x upper normal value (ULN) (unless accompanied by Gilbert's syndrome), and the subject's aspartate aminotransferase (AST / SGOT), alanine aminotransferase (ALT). / SGPT), and alanine phosphatase are ≤2.5 x ULN (≤5 x ULN is allowed if liver metastasis is present).

In some embodiments, the subject has acceptable renal function. In such an embodiment, the subject's calculated creatinine clearance is ≧ 30 mL / min.

In some embodiments, the subject has an acceptable hematological condition. In such an embodiment, the number of granule cells of interest is ≧ 1500 cells / mm ³ , the number of platelets is ≧ 100,000 (plt / mm ³ ), and the hemoglobin is ≧ 8 g / dL. In some embodiments, the subject has not received a blood transfusion within 14 days of the initial administration of the ACVR1 inhibitor.

In some embodiments, the subject has an acceptable coagulation state. In such embodiments, the subject's prothrombin time (PT) is in the 1.5 x normal range and the activated partial thromboplastin time (aPTT) is in the 1.5 x normal range.

In certain embodiments, the subject is 22 years or younger, 21 years or younger, 20 years or younger, 19 years or younger, 18 years or younger, 17 years old or younger, 16 years old or younger, 15 years old or younger, 14 years old or younger, 13 years old or younger, 12 years old or younger, 11 years old Or younger, 10 or younger, 9 or younger, 8 or younger, 7 or younger, 6 or younger, 5 or younger Patients younger, 4 years or younger, 3 years or younger, 2 years or younger, or 1 year or younger. In some embodiments, the patient is a pediatric patient who can be defined as 22 years or younger or 18 years or younger. In other words, in some embodiments, the patient is a child up to 22 years of age. In other embodiments, the patient is a child up to 18 years of age. In some embodiments, the patient is about 3 to about 10 years old. In some embodiments, the patient is about 3 to about 5 years old. In some embodiments, the patient is about 5 to about 10 years old. In some embodiments, the patient is about 6 to about 10 years old. In some embodiments, the patient is about 6 to about 8 years old.

In various embodiments, the ACVR1 inhibitor is an ACVR1 inhibitor of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. Including, it is formulated as a pharmaceutical composition.

Accordingly, the present disclosure provides compositions containing ACVR1 inhibitors used in the methods described herein. In embodiments, the ACVR1 inhibitor is formulated for oral administration. In various embodiments, the ACVR1 inhibitor is formulated as a tablet, capsule (eg, gelatin capsule), or solution. In certain embodiments, the ACVR1 inhibitor is formulated as an excipient. In certain embodiments, the ACVR1 inhibitor is formulated as a gelatin capsule. In some embodiments, gelatin capsules are formulated with a titer of 5 mg, 25 mg, or 125 mg. In some embodiments, the capsule is formulated with a titer of 30 mg, 90 mg, or 120 mg. In certain embodiments, the ACVR1 inhibitor is formulated as an oral solution. In some embodiments, the solution is formulated in 5 mg / mL increments, 10 mg / mL increments, 20 mg / mL increments, or 30 mg / mL increments. In some embodiments, the solution is formulated to provide a pediatric dose between about 80% and about 100% of the adult dose. In some embodiments, the solution is formulated with a titer of about 24 to about 30 mg, about 48 to about 60 mg, about 72 to about 90 mg, and about 96 to about 120 mg. In some embodiments, the solution is formulated with a titer of 30 mg, 60 mg, 90 mg, or 120 mg. In some embodiments, the solution is formulated with a titer of 24 mg, 48 mg, 72 mg, or 96 mg.

The pharmaceutical compositions of the present disclosure can be prepared by combining an ACVR1 inhibitor with a suitable pharmaceutically acceptable carrier, diluent, or excipient and are solid, semi-solid, liquid, or gaseous. It may be formulated into a preparation of the form, for example tablets, capsules, powders, granules, ointments, solutions, suppositories, excipients, inhalants, gels, microspheres, and aerosols. Typical routes for administering such pharmaceutical compositions include oral, topical, transdermal, inhaled, parenteral, sublingual, buccal, rectal, vaginal, and intranasal. As used herein, the term parenteral includes subcutaneous injection, intravenous, intramuscular, intrasternal injection or infusion techniques. The pharmaceutical composition of the present disclosure is formulated so that the active ingredient contained therein is bioavailable after administration of the composition to a patient.

The pharmaceutical compositions of the present disclosure may take the form of solids or liquids. In one aspect, the carrier (s) are granular and thus the composition is in the form of, for example, tablets or powders. The carrier (s) may be liquid and the composition may be, for example, an oral syrup, an injectable solution, or, for example, an aerosol useful for inhalation administration.

Where oral administration is intended, the pharmaceutical composition preferably takes either solid or liquid form, and the semi-solid, semi-liquid, suspension, and gel forms are herein as either solid or liquid. Included in the form considered in the book.

As a solid composition for oral administration, the pharmaceutical composition may be formulated in powder, granules, compressed tablets, pills, capsules, chewing gum, wafers, or similar forms. Such solid compositions typically contain one or more Inactive Diluents or Elemental Edibles. In addition: Binders such as carboxymethyl cellulose, ethyl cellulose, microcrystalline cellulose, tragacant gum, or gelatin; excipients such as denbun, lactose, or dextrin, disintegrants such as alginic acid, sodium alginate, primogel, corn starch; stearic acid Lubricants such as magnesium or sterotex; lubricants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; flavoring agents such as peppermint, methyl salicylate, or orange flavor; and one or more of colorants May be present.

When the pharmaceutical composition is in the form of capsules, such as gelatin capsules, it may contain a liquid carrier such as polyethylene glycol or oil in addition to the above types of materials.

The pharmaceutical compositions used in the methods of the invention may be in the form of liquids such as elixirs, syrups, solutions, emulsions or suspensions. The liquid may be, for example, for oral administration or for delivery by injection. When intended for oral administration, the pharmaceutical composition comprises, for example, one or more of a sweetener, a preservative, a pigment / colorant and a seasoning in addition to the therapeutic compound (s). Compositions intended for administration by injection include one or more of surfactants, preservatives, wetting agents, dispersants, suspending agents, buffers, stabilizers, and isotonic agents. You may.

The liquid pharmaceutical compositions used in certain embodiments of the present disclosure, whether they are solutions, suspensions or other similar forms, are the following adjuvants: water for injection, physiology. Sterilized diluents such as saline solutions, preferably physiological physiological saline, Ringer's solution, isotonic sodium chloride, synthetic monoglycerides or synthetic diglycerides that can act as solvents or suspension media, polyethylene glycol, glycerin, propylene glycol, or Fixed oils such as other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium hydrogen sulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate, and chloride It may contain one or more agents for adjusting tonicity, such as sodium or dextrose. Parenteral preparations can be encapsulated in ampoules made of glass or plastic, disposable syringes, or multi-dose vials. Physiological saline is the preferred adjuvant. The injectable pharmaceutical composition is preferably sterilized. In embodiments, the pharmaceutical composition is formulated for injection. In some embodiments, the pharmaceutical composition is formulated for mass injection. In embodiments, the pharmaceutical composition is formulated for infusion.

The liquid pharmaceutical composition used in the embodiments of the present disclosure, which is intended for either parenteral or oral administration, should contain an amount of ACVR1 inhibitor that provides an appropriate dosage.

In certain embodiments, the ACVR1 inhibitors described herein are administered topically rather than systemically and are often depot-prepared or sustained release, eg, by direct injection of the ACVR1 inhibitor into an organ. It is administered as a preparation. In certain embodiments, the long-acting formulation is administered by implantation (eg, subcutaneous or intramuscular) or by intramuscular injection. In addition, in other embodiments, the drug is delivered in a targeted drug delivery system, eg, as liposomes coated with an organ-specific antibody. In such embodiments, the liposomes target the organ and are selectively taken up by the organ. In yet another embodiment, the compounds described herein are provided in the form of a fast release formulation, in the form of an extended release formulation, or in the form of an intermediate release formulation.

The pharmaceutical compositions used in certain embodiments of the present disclosure may be intended for topical administration, in which case the carrier may appropriately comprise a solution, emulsion, ointment, or gel base. The base may contain, for example, one or more of the following: diluents such as petroleum, lanolin, polyethylene glycol, beeswax, mineral oils, water and alcohols, as well as emulsifiers and stabilizers. The thickener may be present in the pharmaceutical composition for topical administration. If intended for transdermal administration, the composition may include a transdermal patch or iontophoresis device.

The pharmaceutical compositions used in certain embodiments of the present disclosure (eg, in the form of solids or liquids) may include agents that bind to the therapeutic compound (s), thereby assisting delivery. good. Suitable agents that can act in this volume include monoclonal or polyclonal antibodies, proteins, or liposomes.

Delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are examples of delivery vehicles or carriers useful herein. In certain embodiments, organic solvents such as N-methylpyrrolidone are also used. In additional embodiments, the compounds described herein are delivered using a sustained release system, such as a semi-permeable matrix of solid hydrophobic polymers containing therapeutic agents. Various sustained release materials are useful herein. In some embodiments, the sustained release capsule releases the compound from a few weeks to over 100 days. Additional strategies for protein stabilization are used, depending on the chemistry and biological stability of the therapeutic reagents.

In an embodiment, the ACVR1 inhibitor and additional therapeutic agent are formulated together in a liposome formulation.

The pharmaceutical compositions used in certain embodiments of the present disclosure may be prepared by methods well known in the pharmaceutical art. For example, a pharmaceutical composition intended to be administered by injection can be prepared by combining an ACVR1 inhibitor with sterile distilled water so that a solution is formed. In some embodiments, the pharmaceutical composition (s) for administration by the methods of the present disclosure take the form of a liquid in which the therapeutic agent is present in solution, suspension, or both. In some embodiments, when the therapeutic agent is administered as a solution or suspension, the first portion of the agent is present in the solution and the second portion of the agent is in granular form in the liquid base material. Exists as a suspension. In some embodiments, the liquid composition comprises a gel formulation. In other embodiments, the liquid composition is aqueous.

In certain embodiments, useful aqueous suspensions contain one or more polymers as suspending agents. Useful polymers include water-soluble polymers such as cellulose polymers, such as hydroxypropyl methylcellulose, and water-insoluble polymers such as crosslinked carboxyl-containing polymers. Certain pharmaceutical compositions described herein include, for example, carboxymethyl cellulose, carbomer (acrylic acid polymer), poly (methyl methacrylate), polyacrylamide, polycarbofyl, acrylic acid / butyl acrylate copolymer, sodium alginate, etc. And a mucoadhesive polymer selected from dextran.

The pharmaceutical composition also optionally comprises a solubilizer that assists in the solubility of the ACVR1 inhibitor. The term "solubilizer" generally includes agents that result in the formation of micelle or true solutions of the agent. Certain acceptable nonionic surfactants, such as polysorbate 80, are useful as solubilizers, as is possible with eye-acceptable glycols, polyglycols, such as polyethylene glycol 400, and glycol ethers. ..

In addition, the pharmaceutical composition may optionally contain one or more pH adjusters or buffers containing acids such as acetic acid, boric acid, citric acid, lactic acid, phosphoric acid, and hydrochloric acid; sodium hydroxide, Includes bases such as sodium phosphate, sodium borate, sodium citrate, sodium acetate, sodium lactate, and tris-hydroxymethylaminomethane; and buffers such as citrate / dextrose, sodium bicarbonate, ammonium chloride. Such acids, bases, and buffers are included in an acceptable amount to maintain the pH of the composition.

In addition, the pharmaceutical composition will optionally also include one or more salts in the amount required to bring the osmotic concentration of the composition to an acceptable range. Such salts include those having sodium, potassium, or ammonium cations, and chloride, citric acid, ascorbic acid, boric acid, phosphoric acid, bicarbonate, sulfuric acid, thiosulfate, or hydrogen sulfite anion. Suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium hydrogen sulfite, and ammonium sulfate.

Other pharmaceutical compositions include, optionally, one or more preservatives that inhibit microbial activity. Suitable preservatives include mercury-containing substances such as melphen and thiomersal; stabilized chlorine dioxide; and quaternary ammonium compounds such as benzalkonium chloride, cetyltrimethylammonium bromide, and cetylpyridinium chloride.

Surfactants may be added to facilitate the formation of homogeneous solutions or suspensions. Surfactants are compounds that interact non-covalently with the therapeutic compound (s) to facilitate a soluble or homogeneous suspension aqueous delivery system. In embodiments, the pharmaceutical composition comprises one or more surfactants that enhance physical stability. Suitable nonionic surfactants are polyoxyethylene fatty acid glycerides and vegetable oils such as polyoxyethylene (60) hydrogenated castor oil; and polyoxyethylene alkyl ethers and alkylphenyl ethers such as octoxinol 10, octoxinol. Includes 40 and the like.

Yet other pharmaceutical compositions include one or more antioxidants that enhance chemical stability when required. Suitable antioxidants include ascorbic acid and sodium metabisulfite, by way of example only.

In certain embodiments, the aqueous suspension composition is packaged in a single dose, non-resealable container. Alternatively, multiple dose resealable containers are used, which typically include a preservative in the composition.

The pharmaceutical compositions used in some embodiments of the present disclosure may be intended for rectal administration, for example, in the form of a suppository that melts in the rectum and releases an ACVR1 inhibitor. Compositions for rectal administration may contain an oily base as a suitable non-irritating excipient. Such bases include lanolin, cocoa butter, and polyethylene glycol.

The pharmaceutical compositions used in the embodiments of the present disclosure may include a variety of materials that modify the physical form of solid or liquid dosage units. For example, the composition may include a material that forms a coating shell around the ACVR1 inhibitor. The material forming the coating shell is typically inert and may be selected from, for example, sugar, shellac, and other enteric coatings. Alternatively, the active ingredient may be encapsulated in gelatin capsules.

The pharmaceutical composition used in certain embodiments may consist of a dosage unit that can be administered as an aerosol. The term aerosol is used to describe a variety of systems, ranging from those of colloidal nature to systems that utilize pressurized packages. Delivery may be by liquefied or compressed gas, or by a suitable pump system that ejects the active ingredient. The aerosol of the ACVR1 inhibitor may be delivered in a single-phase, two-phase, or three-phase system to deliver the active ingredient (s). Delivery of aerosols includes the necessary containers, activators, valves, sub-containers, etc. that can be combined to form a kit. One of ordinary skill in the art can determine the preferred aerosol without undue experimentation.

In any of the aforementioned embodiments, the ACVR1 inhibitor or pharmaceutically acceptable salt thereof is the activity of the particular ACVR1 inhibitor used; the metabolic stability and length of action of the ACVR1 inhibitor; the age of the patient, Weight, general health, gender, and diet; form and time of administration; excretion rate; combination of drugs; severity of a particular disorder or condition; and effective amount that depends on a variety of factors, including the treatment the subject receives. Is administered.

The toxicity and therapeutic efficacy of the methods described herein can be determined by standard pharmaceutical procedures in cell cultures or laboratory animals, eg, by determining the administered ACVR1 inhibitors IC ₅₀ and LD ₅₀ . Can be decided. For administration, the effective amount (also referred to as dose) can be initially estimated based on results from in vitro assays and / or animal model studies. For example dose comprises an IC ₅₀ when determining the cell culture for a particular target, as circulating concentration range is achieved, can be formulated in animal models. The dosage may vary depending on the dosage form used and the route of administration used. The exact formulation, route of administration, and dosage, in view of the patient's condition can be chosen by the individual physician (e.g., Goodman &Gilman's The Pharmacological Basis Of Therapeutics, Ch. 3, 9 th ed., Ed. by Hardman, J., and Limbard, L., McGraw-Hill, New York City, 1996, p.46).

Compositions administered to a subject may take the form of one or more dosing units, eg tablets may be single dosing units, one or more of the present disclosure in aerosol form. The therapeutic agent container may hold multiple dosing units. Practical methods for preparing such dosage forms are known or manifested to those of skill in the art; see, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). sea bream. In any case, a pharmaceutical composition administered using a particular embodiment of the methods of the present disclosure may be an effective amount of an ACVR1 inhibitor or an amount thereof for treating a disease according to the teachings of the embodiments of the present disclosure. Contains pharmaceutically acceptable salts.

The ACVR1 inhibitors described herein are effective over a wide range of dosages. For example, in adult treatment, dosages of about 5 mg to about 500 mg, about 10 mg to about 320 mg, about 30 mg to about 240 mg, and about 30 mg to about 180 mg per day are used in some embodiments. This is an example of quantity. In some embodiments, the dose is from about 30 mg to about 120 mg per day. In some embodiments, the dose is from about 30 mg to about 60 mg per day. In some embodiments, the dose is from about 60 mg to about 240 mg per day. In some embodiments, the dose is from about 60 mg to about 180 mg per day. In some embodiments, the dose is from about 60 mg to about 120 mg per day. In some embodiments, the dose is from about 120 mg to about 240 mg per day. In some embodiments, the dose is from about 120 mg to about 180 mg per day. In some embodiments, the dose is from about 180 mg to about 240 mg per day.

In certain embodiments, the dose is about 5 mg per day. In certain embodiments, the dose is about 10 mg per day. In certain embodiments, the dose is about 25 mg per day. In other embodiments, the dose is about 30 mg per day. In other embodiments, the dose is about 60 mg per day. In other embodiments, the dose is about 120 mg per day. In certain embodiments, the dose is about 125 mg per day. In other embodiments, the dose is about 180 mg per day. In other embodiments, the dose is about 240 mg per day. In other embodiments, the dose is about 250 mg per day. In other embodiments, the dose is about 320 mg per day. In other embodiments, the dose is about 325 mg per day.

As another example, in adult treatment, dosages of about 5 mg to about 500 mg per week, about 10 mg to about 320 mg, about 30 mg to about 240 mg, and about 30 mg to about 180 mg per week are some embodiments. This is an example of the dosage used in. In some embodiments, the dose is from about 30 mg to about 120 mg per week. In some embodiments, the dose is from about 30 mg to about 60 mg per week. In some embodiments, the dose is from about 60 mg to about 240 mg per week. In some embodiments, the dose is from about 60 mg to about 180 mg per week. In some embodiments, the dose is from about 60 mg to about 120 mg per week. In some embodiments, the dose is from about 120 mg to about 240 mg per week. In some embodiments, the dose is from about 120 mg to about 180 mg per week. In some embodiments, the dose is from about 180 mg to about 240 mg per week.

In certain embodiments, the dose is about 5 mg per week. In certain embodiments, the dose is about 10 mg per week. In certain embodiments, the dose is about 25 mg per week. In other embodiments, the dose is about 30 mg per week. In other embodiments, the dose is about 60 mg per week. In other embodiments, the dose is about 120 mg per week. In certain embodiments, the dose is about 125 mg per week. In other embodiments, the dose is about 180 mg per week. In other embodiments, the dose is about 240 mg per week. In other embodiments, the dose is about 250 mg per week. In other embodiments, the dose is about 320 mg per week. In other embodiments, the dose is about 325 mg per week.

As described herein, the pediatric dose may be between about 80% and 100% of the adult dose.

In some embodiments, the dose is increased. In one embodiment, the dose starts at 30 mg per week and is increased by 30 mg to 120 mg per week. In one embodiment, the dose starts at 30 mg per week and remains at the same level. In one embodiment, the dose starts at 30 mg per week and is increased to a final dose of 60 mg per week. In one embodiment, the dose is started at 30 mg per week, increased to an intermediate dose of 60 mg per week, and further increased to a final dose of 90 mg per week. In one embodiment, the dose starts at 30 mg per week and is increased to a first intermediate dose of 60 mg per week, a second intermediate dose of 90 mg per week, and a final dose of 120 mg per week. Raise. In one embodiment, the dose is started at 60 mg per week and the levels remain unchanged. In one embodiment, the dose starts at 60 mg per week and is increased to a final dose of 90 mg per week. In one embodiment, the dose is started at 60 mg per week, increased to an intermediate dose of 90 mg per week, and further increased to a final dose of 120 mg per week.

In embodiments, ACVR1 inhibitor is administered at a dose ranging from 1 day to about 10 mg / ^{m 2} to about 500 mg / ^{m 2.} In embodiments, ACVR1 inhibitor is administered at a dose ranging from 1 day to about 150 mg / ^{m 2} to about 350 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from 1 day to about 200 mg / ^{m 2} to about 300 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from 1 day to about 220 mg / ^{m 2} to about 260 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from 1 day to about 230 mg / ^{m 2} to about 250 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from 1 day to about 235 mg / ^{m 2} to about 245 mg / ^{m 2.} In certain embodiments, the ACVR1 inhibitor is administered at a dose of ^{about 240 mg / m 2 per day.}

In embodiments, ACVR1 inhibitor is administered at a dose ranging from about 10 mg / ^{m 2} per week to about 500 mg / ^{m 2.} In embodiments, ACVR1 inhibitor is administered at a dose ranging from about 150 mg / ^{m 2} per week to about 350 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from about 200 mg / ^{m 2} per week to about 300 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from about 220 mg / ^{m 2} per week to about 260 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from about 230 mg / ^{m 2} per week to about 250 mg / ^{m 2.} In some embodiments, ACVR1 inhibitor is administered at a dose ranging from about 235 mg / ^{m 2} per week to about 245 mg / ^{m 2.} In certain embodiments, the ACVR1 inhibitor is administered at a dose of ^{about 240 mg / m 2 per week.}

The exact dosage is ACVR1 inhibitor, route of administration, form of administration of the compound, subject to be treated, physical and physiological factors including the target, body weight, severity of condition, type of cancer, pre- or It depends on the concurrent intervention, the subject's idiopathic disease, and the preference and experience of the attending physician.

In some embodiments, an effective amount of the ACVR1 inhibitor is administered in a single dose. Typically, such administration is by injection, eg, intravenous injection, for rapid introduction of the drug. However, other routes are used appropriately. Single doses of the compounds of the present disclosure may be used in the treatment of acute conditions.

In some embodiments, an effective amount of the ACVR1 inhibitor is administered in multiple doses. In some embodiments, the dosing is about once, twice, three times, four times, five times, six times, or more times per day. In some embodiments, the dosing is about once, twice, three times, four times, five times, six times, or more per week. In other embodiments, the dosing is about once a month, once every two weeks, once a week, or once every other day. In yet another embodiment, administration is continued for more than about 6, 10, 14, 28 days, 2 months, 6 months, or 1 year. In some cases, continuous dosing is realized and maintained as long as necessary. In some embodiments, the ACVR1 inhibitor is administered for 1, 7, 14, 21, or 28 consecutive days. In some embodiments, the ACVR1 inhibitor is administered weekly. In some embodiments, the ACVR1 inhibitor is administered at weeks 1, 2, 3, and 4 of the 4-week cycle. In some embodiments, the 4-week cycle comprises one or more holidays. In some embodiments, the 4-week cycle does not include holidays and the dosing is continuous dosing.

In various embodiments, the ACVR1 inhibitor is administered daily. In various embodiments, the ACVR1 inhibitor is administered weekly. In each of such embodiments, the ACVR1 inhibitor is ingested at substantially the same time of the day. In some embodiments, the ACVR1 inhibitor is administered after fasting (eg, at least 6 hours). In certain embodiments, the subject fasts for at least 1 hour after administration.

Administration of the ACVR1 inhibitor can be continued as long as necessary. In some embodiments, the ACVR1 inhibitor is administered for longer than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the ACVR1 inhibitor is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the ACVR1 inhibitor is administered for longer than 1, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, or 52 weeks. In some embodiments, the ACVR1 inhibitor is administered for less than 52, 48, 44, 40, 36, 32, 28, 24, 20, 16, 12, 8, 4, or 1 week.

In some embodiments, the ACVR1 inhibitor is administered continuously over the long term, for example for the treatment of long-term effects.

In some embodiments, the additional therapeutic agent may be administered in the long term (eg, as maintenance therapy). In other such embodiments, one additional therapeutic agent or more is administered as a second treatment regimen.

In some embodiments, the ACVR1 inhibitor is administered at a dosage. Due to inter-subject variations in the pharmacokinetics of compounds, individualization of dosing regimens is provided in certain embodiments. Dosings for therapeutic agents can be found by routine experimentation in the light of the present disclosure and / or can be derived by one of ordinary skill in the art.

Dosing amounts and intervals can be individually adjusted to provide plasma levels of the active species sufficient to maintain the desired pharmacological effect. These plasma levels are referred to as the minimum effective concentration (MEC). The dosage required to achieve MEC depends on the individual characteristics and route of administration. HPLC assays or bioassays can be used to determine plasma concentrations.

Dosing intervals may be determined using MEC values. In some embodiments, the method of treatment comprises maintaining plasma levels higher than MEC for 10 to 90% of the time. In some embodiments, plasma levels are maintained above MEC for 30-90% of the time. In some embodiments, plasma levels are maintained above MEC for 50-90% of the time. For example, in certain embodiments, the effective amount of the therapeutic agent may range from 1 day approximately 2.5 mg / ^{m 2} to 1500 mg / ^{m 2.} For example, in certain embodiments, the effective amount of the therapeutic agent may range approximately from 2.5 mg / ^{m 2} per week in 1500 mg / ^{m 2.} Additional exemplary amounts range from 0.2 to 1000 mg, 2 to 500 mg, and 20 to 250 mg, either daily or weekly.

For topical or selective ingestion, the effective local concentration of therapeutic agent may not be related to plasma concentration, and other procedures known in the art determine the correct dosage and interval of dosing. It may be used for.

In some embodiments, the concentrations of the ACVR1 inhibitor provided in the pharmaceutical composition are 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19 %, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06% , 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005% , 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004% , 0.0003%, 0.0002%, or less than 0.0001% w / w, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19% , 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2 %, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or less than 0.0001% w / v, or 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19% , 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2 %, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002 %, Or less than 0.0001% v / v.

In some embodiments, the concentrations of the ACVR1 inhibitor provided in the pharmaceutical composition are 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%. , 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75 %, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13. 75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%, 11.25% 11%, 10 .75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25%, 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5% 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25 %, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09% , 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008% , 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007% , 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or greater than 0.0001% w / w, 90%, 80%, 70%, 60%, 50 %, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25% 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25% 15%, 14.75% , 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25% 12%, 11.75 % 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50% , 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50 %, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0 .1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0 .009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0 .0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% greater than w / v, or 90%, 80 %, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25 % 18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15. 25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12 .25% 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25% 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50% , 6.25% 6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3. 50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, Greater than 0.0002% or 0.0001% v / v.

In some embodiments, the concentration of ACVR1 inhibitor provided in the pharmaceutical composition is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30. %, About 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25 %, About 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20 %, About 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15 %, About 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / w, about 0.0001% to about 50%, about 0.001% From about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% From about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% From about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% From about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10% w / v or about 0 .0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0 .04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0 .09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0 .5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1 It is in the range of% to about 10% v / v.

In some embodiments, the concentration of ACVR1 inhibitor provided in the pharmaceutical composition is from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4 5.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0 .07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, about 0. 001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5% , About 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% From about 1%, about 0.1% to about 0.9% w / v, or about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about It ranges from 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, and from about 0.1% to about 0.9% v / v.

The ACVR1 inhibitor or pharmaceutically acceptable derivative thereof used in the embodiments of the present disclosure may be administered before or after administration of one or more other therapeutic agents. .. For example, a first therapeutic agent (eg, an ACVR1 inhibitor) can be administered, and after a sufficient period of time, the second therapeutic agent is administered. In such embodiments, the period between administration of the first therapeutic agent and the second therapeutic agent may be referred to as "interruption of treatment" or "holiday". “Treatment interruption” or “holiday” may refer to the period between treatment cycles. In some embodiments, interruptions or holidays of such treatment range from about 12 hours to about 48 hours. In some embodiments, interruptions or holidays of such treatment range from about 18 to about 36 hours. In some embodiments, interruptions or holidays of such treatment range from about 24 to about 48 hours. In some embodiments, treatment interruptions or holidays range from about 2 to about 10 days. In some embodiments, treatment interruptions or holidays range from about 3 to about 5 days. In some embodiments, treatment interruptions or holidays range from about 5 to about 9 days. In some embodiments, the discontinuation or holiday of treatment is about 7 days. In various embodiments, the ACVR1 inhibitor is administered for 21 consecutive days, followed by a 7-day discontinuation of treatment or a holiday. In some embodiments, the discontinuation or holiday of treatment is about 30 days. In various embodiments, the ACVR1 inhibitor is administered weekly for a cycle of 4 consecutive weeks, without interruption of treatment or holidays. One of ordinary skill in the art can derive an appropriate dosing schedule based on common techniques and knowledge. In embodiments, the ACVR1 inhibitor and one or more of radiation therapy and additional therapeutic agents are administered sequentially.

(Example 1)
Experimental ACVR1 Inhibitor Testing Wild-type and Mutant ACVR1 Inhibition Strong biochemical inhibition of wild-type ACVR1, FOP / DIPG mutant R206H, and two additional mutant kinases (G328V and R258G) found in DIPG. Demonstrated compound 2 was tested according to standard assay procedures.

Simply put, a casein-based substrate was prepared. Each ACVR1 kinase was added to the substrate mixture and hot / cold 33P-ATP (10 μM) was added to initiate the reaction. The activity was then measured by the filter binding method.

ＳＭＡＤ１／５リン酸化の阻害 Listed _{IC 50} values in Table 3 below for the kinase.

Inhibition of SMAD1 / 5 phosphorylation

The SMAD protein is a transcription factor involved in signal transduction downstream of the TGFβ receptor. The TGFβ receptor ALK2 phosphorylates SMAD when activated by bone morphogenetic proteins such as BMP2, which expresses genes such as HAMP that encode SMAD nuclear translocation, transcription initiation, and the peptide hormone hepcidin. Bring an increase. Therefore, compounds that target ALK2 should inhibit BMP-induced SMAD phosphorylation. To assess the in vitro potency of compound 2, HepG2 cells were stimulated with the ALK2 ligand BMP2 in the presence or absence of various concentrations of compound 2. The results shown in FIG. 1 reveal a clear concentration-dependent inhibition of SMAD1 / 5 phosphorylation by compound 2 (EC50 = 162 nM).
Inhibition of hepcidin expression

To assess the in vitro potency of compound 2, HepG2 cells were stimulated with ALK2 ligand BMP-2 in the presence or absence of various concentrations of compound 2 and the resulting hepcidin expression levels were qPCR. Measured by. The results shown in FIG. 2A reveal a strong dose-responsive inhibition of hepcidin transcription by compound 2 (EC ₅₀ <1 nM). The effect on underlying hepcidin transcription was also measured (in the absence of BMP-2 stimulation) and the results are shown in FIG. 2B. Under these experimental conditions, compound 2 inhibited hepcidin expression in a manner that is responsive to the dose _{(IC 50} of about 100 nM).

Turpentine (TO) is known to elicit an acute inflammatory response on relevant dip tests in mice, including high hepcidin levels. We used this model to evaluate test compounds for in vivo efficacy (Fig. 3).

These data suggest that hepcidin can be a valuable predictive and / or prognostic marker when assessed before and / or during treatment with Compound 2.
Proliferation assay for DIPG cell lineage

Compound 2 was tested in vitro in a proliferation assay against ACVR1 mutants (G328V mutant cell line) and wild DIPG cell lines. The results performed selective activity against mutant cell lines, similar to the values observed in the pSMAD1 / 5 inhibition assay.
(Example 2)
Pharmacodynamic and toxicological studies of ACVR1 inhibitors

To be an effective treatment for DIPG, compound 2 needs to be distributed in the brain and, more importantly, to achieve very deep penetration into the brain pons region. A preliminary brain PK survey was performed to assess the overall distribution of Compound 2 to the brain. Brain tissue concentration shows a very good distribution to the brain (Fig. 4A). The calculated PK parameters are shown in Tables 4 and 5.

In addition, a comparison of the concentrations of Compound 2 in plasma and brain tissue was performed and the results are shown in FIG. 4B and Table 6.

Another study was conducted to further explore the penetration of Compound 2 into the brain. In this study, mice were administered a single oral dose of Compound 2 and brain tissue was collected 1 and 2 hours after dosing. The concentration of compound 2 was measured in brain tissue sections by MALDI-TOF mass spectrometry.

1 gram of mouse brain cells was mixed with compound 2 at known concentrations ranging from 0.5 μg to 50 μg. Four mice were treated with Compound 2, which was orally administered at 100 mg / kg. Samples were taken before treatment and 1, 2, and 4 hours after treatment. A mouse mimicry model treated with Compound 2 and an actual sample were then analyzed together.

Additional pharmacokinetic and tissue distribution studies were performed to comprehensively assess compound 2 exposure in multiple mouse organs. CD-1 male mice were dosed with 20 mg / kg PO with compound 2 formulated in 20% saltol and 80% saline. Plasma and organs were collected at 9 time points and drug concentrations were determined by LC-MS / MS. Compound 2 was detectable in all collected tissues, and most of the tissues demonstrated high drug concentrations compared to plasma. The results confirmed exposure in clinically relevant target organs, including the brain and liver (Table 7).

Compound 2 free base was tested in humans. The oral pharmacokinetics of compound 2 were determined in one human patient for the treatment of DIPG. The pharmaceutical product was free base compound 2 with a rest period of 15 days, then 20 days, daily with gelatin capsules. Dosing was resumed by dissolving in juice and administered via the nasogastric tube for 9 days. The nominal dose is 240 mg / m2 (PO). Blood samples are collected at 4 time points and drug concentrations are determined by LC-MS / MS.

Orally administered compound 2 was absorbed and detected in plasma 24 hours after dosing in one human, with a long-term return to baseline. Additional PK parameters were evaluated.

The pharmacokinetics and toxicology of Compound 2 was tested in rats. Intravenous (IV) and oral (PO) pharmacokinetics of Compound 2 were determined in the plasma of fasted female Sprague-Dawley (SD) rats. The formulations used were 20% saltol and 80% saline for both routes of administration. Nominal doses were 2 mg / kg (IV) and 20 mg / kg (PO). Samples were taken at 8 time points and drug concentrations were determined by LC-MS / MS. Plasma concentrations for IV and PO administration are shown in FIG. 5, and PK calculations from this data are shown in Table 8.

In non-GLP toxicology studies, SD rats were administered 400, 200, or 100 mg / kg of compound 2 HCl salt in 20% saltol or vehicle control for 7 days.
(Example 3)
Dose response controlled trials

The effect of compound 2 on cell viability in 7 cell lines was investigated. A 50% inhibitory concentration (IC ₅₀ ) was determined in selected cell lines using the CellTiter-Glo luminescence cell viability assay after incubation at various test product concentrations.

The cell line was treated 3 times with 9 concentrations of Compound 2, cisplatin was used as a reference compound, and 0.5% (v / v) DMSO was added to the culture medium as a vehicle control.
Materials and Reagents Common cell culture reagents and plastics.
96-well flat clear bottom black polystyrene TC-treated microplate (Cat # 3340, Corning).
Back Seal Black Adhesive Bottom Seal (Cat # 6005189, Perkin Elmer).
CellTiter-Glo® Luminescence Cell Viability Assay (Cat. # .: G7572, Promega. Stored at -20 ° C)
The substrate is sufficient for 1,000 assays in 100 μl per assay in 96-well plates.
Including:
1 × 100 mL CellTiter-Glo® buffer ・ 1 × vial CellTiter-Glo® substrate (lyophilized)
Reagent Preparation CellTiter-Glo buffer was thawed, equilibrated to room temperature and then used.
The lyophilized CellTiter-Glo substrate was equilibrated to room temperature and then used.
The appropriate volume (100 mL) of CellTiter-Glo buffer was transferred to an amber bottle containing the CellTiter-Glo substrate and the lyophilized enzyme / substrate mixture was replaced. As a result, the CellTiter-Glo reagent was formed.
The contents were mixed by gently stirring to form a vortex or inversion to give a homogeneous solution.
Determining Maximum Half Inhibition Concentration IC ₅₀ Cells were harvested during the logarithmic growth period and the number of cells was counted using a count star.
The cell concentration ^{was adjusted to 3.33 × 10 4} cells / mL in culture medium.
90 μL of cell suspension was added to three 96-well plates (plates A and B) to a final cell density of 3 × 10 ³ cells / well (cell concentration adjusted according to database or density optimization assay). NS).
Regarding the T0 reading plate:
10 μL of culture medium was added to each well of plate A for T0 reading.
The plate and its contents were equilibrated at room temperature for approximately 30 minutes.
A black sticker was placed on the bottom of the plate to block the light.
100 μL of CellTiter-Glo was added to each well.
The contents were mixed on an orbital shaker for 2 minutes to induce cytolysis.
The plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal.
Luminescence (T0) was recorded using an EnVision multi-label reader.
Regarding the test reading plate:
A 10 × solution (concentration of action: 10 μM) test was serially diluted 3.16 times in medium to achieve 10 dose levels.
10 μL (10 ×) drug solutions of both the test and reference controls were dispensed into each well of plate B (3 times for each drug concentration) (final solvent concentration in culture medium: 0.5% [v). / V]).
Test plate B was incubated for 72 hours in a humidified incubator at 37 ° C. containing _{5% CO 2 and then measured using the CTG assay.}
The plate and its contents were equilibrated at room temperature for approximately 30 minutes.
A black sticker was placed on the bottom of the plate to block the light.
100 μL of CellTiter-Glo was added to each well.
The contents were mixed on an orbital shaker for 2 minutes to induce cytolysis.
The plate was incubated at room temperature for 10 minutes to stabilize the luminescence signal.
Recorded luminescence.
Data analysis

The data were graphed using GraphPad Prism 5.0.

To calculate the absolute IC ₅₀ (EC ₅₀ ), the dose response curve was fitted with an S-shaped dose response using a non-linear regression model. The formula for calculating the survival rate is shown below, and the absolute IC ₅₀ (EC ₅₀ ) was calculated according to the dose response curve created by GraphPad Prism 5.0.

Survival rate (%) = (Lum test-Lum medium control) / (Lum untreated-Lum medium control) x 100%.

FIG. 6A shows the dose response curve for the IGR-OV1 cell line. IGR-OV1 is an ACVR1 mutant (P455A) cell line. FIG. 6B compares the results of the IGR-OV1 (mutant ACVR1) cell line against C-33a, SK-OV-3, AN3-CA, CaSki, HeLa, and HEC-1-A (wild-type ACVR1). show.
(Example 4)
in vivo jar cut xenotransplantation model

The effect of compound 2 on tumor volume in a xenograft model was investigated. Animals were housed under the following conditions:
Animals were housed in a ventilated mouse cage system (Animal Care Systems, Centennial, CO) at regulated temperature and light / dark cycles.
Temperature: 22.7 to 23.9 ° C
Humidity: 10%
Sleeping straw: Corn cob (Animal Care Systems, 1/4 "irradiation)
Diet: Whole irradiation, no soy protein, extruded rodent diet (Envigo, Cat.No: 2920X.CS)
Water: RO water, voluntary

Jarkat cells were cultured in RPMI 1640 medium supplemented with 10% FBS and incubated with _{5% CO 2 at 37 ° C.} Cells were subcultured twice weekly or as needed.

Cells were washed with serum-free medium and then suspended in 1: 1 serum-free medium: Matrigel. The injection volume was 200 μL. The flank after the mice, the 1 × 10 ⁷ cells / mouse were injected subcutaneously.

Animal tumor volume and body weight were measured and recorded twice weekly. Treatment was initiated when the tumor volume reached> 100 mm ^3. Mice were stratified by tumor volume to obtain a similar average starting tumor volume for each animal cage, and then each cage was randomly selected and placed in the treatment group.

Tumor volume measurements were performed twice weekly using calipers that measure both length (longest diameter) and width (perpendicular to the longest diameter). Tumor volume was calculated as L × W × W / 2.

50 mg / kg (Qd) of the HCl salt of Compound 2 was formulated in 20% saltol and 80% dextrose (5% dextrose solution) and administered to mice. The results are shown in FIG.
(Example 5)
Analysis of ACVR1 mutations in adult cancer

The genetic structure of the ACVR1 mutation was analyzed to assess which mutations could signal benefits from treatment with compounds of structure (I). A publicly available sequence database and analysis tool, cBioPortal. The org was used to analyze ACVR1 mutations in the tissues of cancer patients. Results were compared to known mutations or gain-of-function activity of ACVR1 in various cancer-related literature. Multiple mutations were found in ACVR1. The FOP community has undertaken extensive work to identify and understand mutations that may promote aberrant activation of ACVR1. These mutations include L196P, R206H, Q207E, R258S, G328E / R, and G356D. The ACVR1 mutations identified in adult cancer include most of the known FOP mutations, but have a greater variety of their ACVR1 mutation profiles with less "hot spots" and many alterations of unknown significance. Also demonstrate. The results of investigating these rare mutations in multiple cancer types are presented herein.

Biochemical studies show that mutations in the intracellular domain may have an activating effect on ACVR1 / ALK2 kinase activity. Many of the known mutations increase the activity of the receptor in response to the receptor ligand. As shown in FIG. 8, Compound 2 was effective in inhibiting the ALK2 receptor with various mutations.

cBioPortal. Using an org browser, The Cancer Genome Atlas (TCGA) pan-cancer and Memorial Sloan Kettering (MSK) IMPACT databases were probed for mutations in ACVR1. FIG. 9A shows a lollipop diagram showing the distribution of ACVR1 mutations; it contains several replication mutations (hotspots) in the glycine-serine regulatory domain and the protein kinase domain that are thought to play a role in regulating ALK2 activity. .. FIG. 9B shows the distribution of several types of chromosomal abnormalities (mutations, amplifications, deletions, and fusions) found across various adult tumor types. FIG. 9C shows a Kaplan-Meier curve showing that subjects with genetic abnormalities in ACVR1 have a 6-month shorter survival time compared to subjects without ACVR1 alterations. The analysis focused on mutation and fusion of ACVR1.

As shown in Table 9, MSK Impact and TCGA database statistics show that a total mutation rate of 0.69% for ACVR1 was found in 147 endemic subjects from a population of 21289 patients.

Analysis of mutations by tumor type showed that of the 147 endemic patients with ACVR1 mutations, 34% had gynecologic cancer, 18% had gastrointestinal cancer, and 14% had breast cancer. However, 13% have melanoma, 6% have urogenital cancer, 5% have neurological cancer, 4% have head and neck cancer, and 3% have other cancers. And 2% had breast cancer.

Table 10 shows the top mutation frequencies classified by amino acid position.

A total of 117 unique mutations were found across the tumor types in the database used. Many of the canonical mutations associated with FOP and DIPG are the most common found at the same location in various adult cancers such as R206H, R375C / H, G356D, G328W / E / V / R, R258G / W. Was in a typical mutation. Many novel mutations of unknown significance have also been detected, suggesting additional genetic changes that may play a role in cancer. CBioPortal. Using the Mutation Assessor, SIFT, and PolyPhen2 algorithms. Impact assessment from org was performed to predict the impact of mutations on protein function.

Table 11 shows the ACVR1 mutations identified in the dataset that were predicted to have adverse effects by the SIFT algorithm. The SIFT algorithm predicted that 55% of mutations would be detrimental, 35% of mutations would be tolerated, and 10% of mutations would have unidentified effects.

Table 12 shows the ACVR1 mutations identified in the dataset that were predicted by the Polyphen2 algorithm to have the potential or likely to cause damage. The Polyphen2 algorithm has the effect that 48% of the mutations are likely damaging, 10% of the mutations are likely damaging, and 31% of the mutations are. It was benign and predicted that 11% of the mutations would have an unidentified effect.

Table 13 shows the ACVR1 mutations identified in the dataset that were predicted by the Mutation Assessor algorithm to have high, moderate, or low impact. The Mutation Assessor algorithm shows that 8% of mutations have a high impact, 28% of mutations have a moderate impact, 35% of mutations have a low impact, 19% of mutations have a neutral impact, and mutations. It was predicted that 10% would have an undefined effect.

These algorithms show that both canonical and endemic mutations can affect protein function. Using the SIFT algorithm, all canonical mutations found in our study were classified as detrimental, which would be a useful tool for predicting the activation of mutations in the ACVR1 gene. Suggests to get. In some cases, different amino acid substitutions at specific sites had different effects on the effects of mutations. Further investigation of these predictive algorithms is guaranteed.

Specific cancer subtypes were then analyzed for the presence of the most common mutations or known activation mutations at various anatomical sites, and SIFT impact scores were calculated by cancer subtype.

Gynecologic cancer. Gynecologic cancers are responsible for most mutations (43) and contained many of the canonical mutations found in FOP and DIPG. The SIFT algorithm shows that among patients with ACVR1 mutations and gynecological cancers (n = 50), 45% of patients have mutations with adverse effects and 40% have mutations with acceptable effects. And 15% predicted to have mutations with undefined effects. Known activations and / or common mutations identified in a subset of gynecologic cancers are shown in Table 14.

Gastrointestinal cancer. The SIFT algorithm has an ACVR1 mutation and among patients with gastrointestinal cancer (n = 27), 52% of the patients have a detrimental effect mutation and 40% have an acceptable effect mutation. It was predicted that 8% would have an influential mutation that has not yet been defined. Known activations and / or common mutations identified in the gastrointestinal cancer subgroup are shown in Table 15.

Chest cancer. The SIFT algorithm shows that in patients with ACVR1 mutations and breast cancer (n = 21), 76% of the mutations have adverse effects, 14% have acceptable effects, and 10% are still defined. Predicted no impact. Known activations and / or common mutations identified in breast cancer are shown in Table 16.

melanoma. The SIFT algorithm shows that among patients with ACVR1 mutations and melanoma (n = 19), 58% of the patients have a detrimental effect mutation and 32% have an acceptable effect mutation, 11 % Was predicted to have an influential mutation that has not yet been defined. Known activations and / or common mutations identified in the subset of melanoma are shown in Table 17.

（実施例６）
進行固形腫瘍を持つ患者に経口投与される式２の化合物の、ヒト初回調査のための臨床試験調査の設計 Nerve cancer. Neurocancer demonstrated a high incidence (30%) of canonical mutations. The SIFT algorithm predicted that of patients with ACVR1 mutations and neurocancer (n = 7), 100% of the patients would have a detrimental mutation. Known activations and / or common mutations identified in the subgroup of neuronal carcinomas are shown in Table 18.

(Example 6)
Design of clinical trial study for initial human study of compound of formula 2 orally administered to patients with advanced solid tumors

The Phase Ia portion of the study comprises a 3 + 3 modified dose escalation for patients with advanced or progressive solid tumors. Dosing is calculated based on body surface area, with dosing taking place for 21 consecutive days in a 28-day treatment cycle. Up to 20 subjects are registered. The archived tissue is required to be genetically tested for patients enrolled in the Phase Ia portion of the study, and next-generation sequencing is performed on the archived tissue to determine the ACVR1 mutant state.

After determining the maximum tolerated dose, additional subjects are enrolled in the Ib phase portion of the test. Enrolled patients have a systematically confirmed diagnosis of advanced metastases or progressive solid tumors. Enrolled patients also become ineffective or intolerant of established treatments that are known to provide clinical benefits to those conditions. In the Ib phase portion, dosing is calculated based on body surface area, with dosing taking place over 21 consecutive days in a 28-day treatment cycle. The archive tissue is required to be genetically tested for patients enrolled in the Ib phase portion of the study, and next-generation sequencing is performed on the archive tissue to determine the ACVR1 mutation status.

The alternative regimen is once a week based on the potency and half-life of Compound 2. Other alternative regimens are 2 doses per week, 3 doses per week, 4 doses per week, 5 doses per week, or 6 doses per week. Each such regimen comprises one cycle of dosing every four weeks. Therefore, one regimen is once weekly over a 4-week cycle and can result in weekly continuous dosing without holidays. Alternative cycles include one or more holidays, eg, dosing for 3 weeks and holidays for 1 week, dosing for 2 weeks and holidays for 2 weeks, dosing for 1 week and holidays for 3 Weeks, or dosing weeks and holiday weeks alternate, that is, dosing is one week and holidays are one week, or dosing is biweekly. For all of these embodiments, the dose of Compound 2 may be level or elevated. Some starting doses may range from about 24 to 30 mg. Some starting or elevated doses may range from about 48 to 60 mg. Additional elevated doses may range from about 72 to 90 mg and about 96 to 120 mg. In one embodiment, the starting dose may be about 60 mg weekly and this value is maintained or increased to about 90 mg weekly. A weekly dose of about 90 mg may be maintained or increased to about 120 mg weekly.
(Example 7)
Oral solid preparation

（実施例８）
経口液体製剤 Hydrochloride of Compound 2 was formulated into three oral dose titers (5, 25, and 125 mg doses [for free base]). The increased amount of active pharmaceutical ingredient was formulated into three similar blends. See Table 19. The product was formulated for immediate release using common excipients during blending. The drug was placed in # 3, hard gelatin capsules.

(Example 8)
Oral liquid preparation

Considering the pediatric population for DIPG therapy, oral liquid formulations have been developed for Compound 2, for example, rather than in tablet or capsule form. Compound 2 has a pronounced bitterness, and therefore the liquid formulation required considerable analysis and evaluation.

First, as shown in Table 20, various excipients were screened as buffers under storage conditions (initially 60 ° C 1, 2, 4W, 40 ° C 2, 4W, 5, 25 ° C 4W). ).

Excipients were screened for precipitation and degrading impurities. For precipitates, little change was observed under pH 3 conditions, but precipitates were found in many samples under pH 4 and pH 5 conditions. With respect to impurities, the degradation appeared to be pH dependent, with pH 5 and pH 4 causing more degradation than pH 3. The least degradation was observed at pH 3 with 10 mM malate buffer. Malate buffer was more chemically and physicochemically stable compared to other tested buffers.

Next, as shown in Table 21, various excipients were screened as preservatives under storage conditions (initially 60 ° C 1, 2, 4W, 40 ° C 2, 4W, 25 ° C 4W, 5). ° C. 4W), the pH of each sample was adjusted to the target pH with NaOH or HCl after dissolution of compound 2.

Excipients were screened for precipitation and degrading impurities. Precipitation was found in samples containing sodium benzoate in citric acid and malate buffers. In terms of degradation, preservatives did not demonstrate significant differences, but propylene glycol appeared to result in minimal degradation. Benzoic acid was considered to be the most suitable preservative, based on its chemical stability and preservative effect under acidic conditions.

Next, as shown in Table 22, various excipients were screened as flavoring agents under storage conditions (initially 60 ° C 1, 2, 4W, 40 ° C 2, 4W, 25 ° C 4W, 5). ° C. 4W), the pH of each sample was adjusted to the target pH with NaOH or HCl after dissolution of compound 2.

Excipients were screened for precipitation and degrading impurities. With respect to precipitation, glycerin resulted in minimal precipitation, but the overall excipients appeared to be similar. In terms of degradation, glycerin resulted in minimal degradation, but the overall excipients appeared to be similar. Screening results did not produce the preferred drug, so in vitro sensory tests were performed among all of the flavoring agents. For more information on taste sensors, see the manufacturer of Insent ™, Intelligent Sensor Technology, Inc. From, for example, http: // www. insent. co. jp / en / index. It can be found in html. A review article published by Tahara and Toko, Electronic Tongues --A Review, IEEE Sensors Journal, Volume 13, No. 8, pp 3001-11, August 2013, can be further referenced. Each of these is incorporated herein by reference with respect to taste sensor technology.

Table 23 provided the test samples investigated in vitro sensory studies, estimated bitterness by "relative value" and "CPA value", and then converted to kinin concentration for each of the test samples.

The results of the test are presented in FIG. The kinin threshold is about 0.03 mM (3.00E-02). Masking bitterness with artificial sweeteners such as sucralose is considered to be "functional masking" and therefore the sensor output is inadequate. However, if the artificial sweetener concentration in the solution is known, it is possible to calculate the predicted value of how much bitterness is suppressed and the actual sensor output at that time. Based on sensor response, 15% HP-β-CD / 0.1% sucralose has a flavoring ability.

Table 24 provides a second set of test sample surveys for in vitro functionality studies.

The results of the test are presented in FIG. Based on sensor response, 15% HP-β-CD / 0.1% sucralose has a flavoring ability.

Preservation efficacy studies were performed with reference to USP40 incorporated herein by reference with respect to such protocols. All prototype formulations have passed the criteria for antimicrobial efficacy required for Category 3 products. However, viable cell counts of Aspergillus brasiliensis were monitored and therefore additional drug investigations and storage studies were performed. In this case as well, USP40 is referred to. The formulations are listed in Table 25.

All prototype formulations passed the 14-day and 28-day criteria for antimicrobial efficacy required for Category 3 products. The storage efficacy was found to be pH dependent. A formulation having 0.2% benzoic acid and pH 2 is believed to provide a better preservative effect.

One embodiment of the oral liquid preparation is described in Table 26.

（実施例９）
塩評価および多形スクリーン Alternative embodiments for oral liquid formulations are shown in Table 27.

(Example 9)
Salt rating and polymorphic screen

The salt screening evaluated the basic compound, compound 2 to assess whether the salt form could provide a benefit over the free base form. For any suitable salt candidate identified, preliminary polymorphic screening may be performed to assess its polymorphic risk.
Overview

Salt screening was performed under 33 conditions using 10 acids (2 mol ratio HCl) and 3 solvent systems. A total of 12 crystalline hits were isolated from all of the screening tests and characterized by X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). The chemical ratio of salt hits ^{was determined by a combination of proton nuclear magnetic resonance (1} H NMR) or high performance liquid chromatography (HPLC) with ion chromatography (IC). Based on the physical properties of the hits, anhydrous HCl salt form A and fumarate form A were selected as precedents for the salts for evaluation.

The precedents for the salts of HCl salt form A and fumarate form A were prepared to a scale of 300 mg, hygroscopic, kinetic solubility in buffers at pH 2, 5, and 7, and at 40 ° C./75% RH. The solid state solubility underneath was evaluated for 1 week. As indicated by the evaluation results (using free base form A as a reference):
a) Free base form A, HCl salt form A, and fumarate form A were all slightly hygroscopic in the absence of morphological changes after the DVS test;
b) Compared to free base form A, HCl salt form A showed increased solubility in buffers of pH 2, 5, and 7, and disproportionation was observed in buffers of pH 7. Fumalate form A showed reduced solubility in buffers of pH 2 and 5 with morphological changes observed, whereas increased solubility in buffers of pH 7 with no morphological changes. Observed; and c) Free base form A, HCl salt form A, and fumarate form A all exhibited good physicochemical properties for 1 week at 40 ° C./75% RH. The results of characterization and evaluation are summarized in Table 28.

−−：入手できなかった
＊：残された非常に少量の遊離塩基形態Ａによって引き起こされ得る
＊＊： ２５℃／８０％ＲＨでの水摂取に基づく：非常に吸湿性がある−＞１５％、吸湿性がある−２〜１５％、僅かに吸湿性がある−０．２〜２％、非吸湿性−＜０．２％

＊：化学量論比は、ＨＰＬＣ／ＩＣによって決定された。＊＊：試料は、蒸発によって得られた。
−−：試料の限られた量に起因して測定されていない。 Based on the results collected, HCl salt form A is the preferred candidate form. Therefore, the polymorphism evaluation survey was conducted with the HCl salt (mono). Starting with HCl salt form A, pre-polymorph screening was performed under 32 conditions using various methods of slurry conversion, evaporation, slow cooling, and backsolvent addition. Based on XRPD comparisons, apart from HCl salt form A, five additional crystalline forms (HCl salt forms C to G) were obtained from screening and characterized by TGA and DSC. Based on the findings, the HCl salt forms A and C were presumed to be anhydrides and hydrates, respectively. Repreparation of the HCl salt forms D and E by evaporation resulted in a mixture containing the HCl salt forms C + D and C + E, respectively. As a result of ¹ H NMR and heating experiments of the mixture, the HCl salt forms D and E may be hydrates. Due to the limited amount of material, potential HCl salt forms F and G were not identified. Detailed characterization data and XRPD overlays for HCl salt morphology obtained from both salt and polymorphic screening are summarized in Tables 29A, 12 and 13A and 13B. FIG. 12 shows the XRPD pattern of HCl salt form A. FIG. 13A shows overlays of HCl salt crystal forms A, C, D, and E. FIG. 13B shows forms B, F, and G. Each form may be referred to as a "type" and the terms are used synonymously.

-: Not available *: Can be caused by a very small amount of free base form A left **: Based on water intake at 25 ° C / 80% RH: Very hygroscopic-> 15% , Hygroscopic-2 to 15%, Slightly hygroscopic -0.2 to 2%, Non-hygroscopic- <0.2%

*: The stoichiometric ratio was determined by HPLC / IC. **: The sample was obtained by evaporation.
−−: Not measured due to the limited amount of sample.

As described, FIG. 12 shows the XRPD pattern of HCl salt form A. The tabular form of the XRPD for Form A is as shown in Table 29B, and the error range ± is described as about 0.2 ° 2θ as understood by those skilled in the art:

As a result of the preliminary salt screening of compound 2 and the polymorphic screening of the HCl salt (mono), monoHCl salt form A is a good candidate for further development.
Details: Salt screening and salt precedent re-preparation

According to the estimated pKa values of 7.5 and 5.1, and the approximate solubility of the free base (812608-05-A) at room temperature (room temperature, 25 ± 3 ° C.), 10 salt forming agents and 3 solvent systems were used. Used for screening. The selected solvent is dispersed in a glass vial on the free base (about 15 mg) and the corresponding salt-forming agent has a 1: 1 molar charge ratio (1: 1 and 2: 1 for HCl / free base). Both two ratios were used). The mixture of free base and acid was stirred at room temperature for 3.5 days. To obtain more solid hits, the resulting clear solution (812608-08-B0 / B5 / B10) was transferred to 5 ° C. and stirred for an additional 2.5 days. Finally, 0.5 mL of n-heptane was added to a clear solution of 812608-08-B0 / B10, and the mixture was stirred at 5 ° C. for another 2 days.

ＦＢ：遊離塩基

＊：黄色粉末は、硫酸塩に関して９９．６１面積％のＨＰＬＣ純度により得られ、その他のヒット全ては白色粉末であった。
塩の先例の再調製および特徴付け All of the obtained solids were isolated, dried at 50 ° C. for 2.5 hours and then analyzed by XRPD. As summarized in Table 30, a total of 12 crystalline hits were obtained, characterized by XRPD, TGA, and DSC, and their stoichiometric quantities were determined by ¹ H NMR or HPLC / IC. The characterization data are summarized in Table 31.

FB: Free base

*: The yellow powder was obtained with an HPLC purity of 99.61 area% relative to the sulfate and all other hits were white powder.
Precedent repreparation and characterization of salts

ＨＣｌ塩形態Ａ Based on the characterization results, the two salt precedents (HCl salt form A and fumarate form A) were recognized as salt precedents and were reprepared to hundreds of milligrams. Selection criteria include: 1) sharp XRPD peaks with no apparent amorphous halo, 2) negligible weight loss at TGA, and 3) net thermal events with sharp melting peaks at DSC. , Not limited to these. The detailed preparation procedure is described in Table 32 and the characterization data are summarized in Table 28 above.

HCl salt form A

HCl salt form A was successfully reprepared, as evidenced by the XRPD results in FIG. According to the TGA and DSC data of FIG. 15, the sample showed a weight loss of 1.7% up to 150 ° C. and three endothermics at 196.2, 214.8, and 274.0 ° C. (starting temperature). rice field. The small endotherm at 196.2 ° C. can be caused by the melting of the very small amount of free base form A left behind. As shown in FIG. 16, after heating the HCl salt form A sample to 218 ° C, heat generation was observed around 202.0 ° C during cooling, and the DSC of the sample obtained after heating was still 213.8 and It showed endothermic at 273.9 ° C. (starting temperature). The signal at 213.8 ° C. can be triggered by morphological transitions, combined with the fact that no morphological changes were observed after heating the sample to 218 ° C., cooling to the original room temperature and exposing to ambient conditions. It was guessed. The stoichiometric ratio was determined by HPLC / IC to be 0.97 (acid / base). A limited gradual TGA weight loss prior to 150 ° C. and a non-significant thermal event at DSC prior to 190 ° C. were observed, suggesting that the sample is an anhydrous HCl salt.
Fumarate form A

Fumarate form A was successfully reprepared, as evidenced by the XRPD results in FIG. 17, showing the XRPD overlay of the fumarate form A batch. According to the TGA and DSC data of FIG. 18, the sample showed 1.0% weight loss up to 150 ° C. and two endothermics at 228.5 and 233.9 ° C. (peak temperature). The stoichiometric ratio was ^{determined to be 0.94 (acid / base) by 1 1} H NMR (FIG. 19), and a limited EtOH residue was detected (about 1.6%). A limited TGA weight loss before 150 ° C., a non-significant thermal event at DSC before 200 ° C., and a limited solvent residue were observed, suggesting that the sample is fumarate anhydride.
Evaluation of salt precedent

Further assessment studies on hygroscopicity, kinetic solubility, and solid state stability were carried out with reference to free base form A to better understand the physicochemical properties of the precedents of the two salts.
Hygroscopic

DVS isotherm plots were collected at 25 ° C. to investigate solid morphological stability as a function of humidity. All anhydrous samples were pre-equilibriumed at 0% Rhes to remove unbound solvent or water before starting. Both the free base form A and the two salt forms are slightly hygroscopic and solid morphological changes after DVS evaluation, as evidenced by the uptake of 0.60 to 1.04% water up to 80% RH. Was not observed (FIGS. 20A, 20B, 20C, 20D, 20E, and 20F).

A significant increase in water uptake (4.56%) was observed for fumarate type A at 95% RH, whereas with HCl salt type A only 1.40% water uptake was observed at 95% RH. It was observed.
Kinetic solubility

The kinetic solubilities of the two salts were measured in buffers of pH 2, 5, and 7 and their solubilities and insolubilities were measured using free base form A (812608-05-A) as a control. The leveling risk was evaluated. All of the solubility samples (initial solid load is about 10 mg / mL) were left rolling on a rolling incubator at a rate of 25 rpm at room temperature (19 ± 3 ° C.) at 1, 2, 4, and 24 hours, respectively. Sampled. After centrifugation, the supernatant was collected for HPLC and pH testing and the wet cake was collected for XRPD characterization. If a clear solution was obtained, the exact concentration was measured with respect to the solution.

Ｓ： ｍｇ／ｍＬを単位とする溶解度、ｐＨ：上澄みの最終ｐＨ、ＦＣ：固体形態の変化。
Ｇ：ゲル様物質が得られたので、データを収集しなかった。
Ｎ／Ａ：分析用の固体なし。＊：１つの余分なブロードピークが２θ≒７．６°で観察された。
固体状態安定性 The results are summarized in Table 33A and the kinetic solubility profile is shown in FIG. 21 (dashed line indicates that a clear solution was obtained). Compared to free base form A, HCl salt form A showed increased solubility in buffers at pH 2, 5, and 7. No solids were obtained with buffers of pH 2 and 5. For pH 7 buffers, morphological changes to free base form A were observed after HCl salt type A was suspended for 1, 2, and 4 hours (limited solids of 1 and 2 hours). Obtained at time point, one special broad peak was observed at 2 hours). The new diffraction peak was observed after 24 hours. Fumarate form A showed decreased solubility in buffers of pH 2 and 5, and morphological changes were observed, but increased solubility was observed in buffers of pH 7, and there was no morphological change. In the case of free base form A, morphological changes were observed except that after suspending free base form A at pH 5, one special Broad Peak (emphasized) was observed at 1 and 2 hours. There wasn't.

S: Solubility in mg / mL, pH: Final pH of supernatant, FC: Change in solid form.
G: No data was collected as a gel-like substance was obtained.
N / A: No solid for analysis. *: One extra Broad Peak was observed at 2θ≈7.6 °.
Solid state stability

ＦＣ：ＸＲＰＤ結果に基づく形態変化。 The solid state stability of free base form A, HCl salt form A, and fumarate form A was evaluated at 40 ° C./75% RH for 1 week. Stability samples were characterized by XRPD to check for any solid morphological changes and by HPLC to check for purity changes. All of the results are summarized in Table 33B and the XRPD data are shown in FIG. 22, which shows that no morphological changes or significant reductions in HPLC purity were observed after the stability test and the free base morphology under test conditions. It shows good physicochemical stability of A and both salts.

FC: Morphological change based on XRPD results.

Based on the collected results, HCl salt form A is a candidate form.
Polymorphic evaluation of HCl salt (mono)

Therefore, a polymorphic evaluation study was conducted on the HCl salt (mono). Preliminary polymorph screening was performed under 32 conditions using methods of slurry conversion, evaporation, slow cooling, and backsolvent addition. Based on the XRPD comparison, in addition to HCl salt form A, five new crystalline forms (HCl salt forms C to G) were obtained from screening and characterized by TGA and DSC. Based on the findings, HCl salt form C was presumed to be a hydrate. Repreparation of the HCl salt forms D and E by evaporation resulted in a mixture containing the HCl salt forms C + D and C + E, respectively. As a result of ¹ H NMR and heating experiments of the mixture, the HCl salt forms D and E may be hydrates. Due to the limited amount of material, potential HCl salt forms F and G were not completely identified.
Anhydrous HCl salt form A

水和物ＨＣｌ塩形態Ｃ HCl salt form A (812608-16-A) was reprepared for polymorphic screening and detailed preparation procedures are shown in Table 34. As shown in FIG. 23, HCl salt type A was successfully reprepared. As shown by the TGA and DSC data in FIG. 24, a 2.0% weight loss up to 150 ° C. and two endothermic peaks (starting temperatures) at 220.7 and 274.8 ° C. were observed. The stoichiometric amount of acid / free base was determined by HPLC / IC to be 1.01. Due to the limited TGA weight loss and the net DSC curve, HCl salt form A was presumed to be anhydrous.

Hydrate HCl salt form C

HCl salt form C (812608-21-A2) was _{obtained from evaporation of CHCl 3} / MeOH (1: 1, v / v) solution (FIG. 25). As shown by the TGA and DSC data in FIG. 26, 3.1% weight loss up to 150 ° C., broad endothermic peaks at 98.8 ° C., and 267.5 ° C. and 275.5 ° C. (peak temperatures). Two sharp peaks were observed. The stoichiometric amount of acid / free base was determined by HPLC / IC to be 1.01.

Heating experiments were performed to identify HCl salt form C. HCl salt type C a (812608-27-B) was heated to 170 ° C. under _{N 2,} it was cooled to 30 ° C., after exposure to ambient conditions, morphological changes were observed. However, the HCl salt form C became the HCl salt form A after being heated to 260 ° C. with the lid open (beyond the endothermic at 264.9 ° C. with the lid closed). See FIG. 27. In addition, after heating HCl salt form C (812608-27-B) to 170 ° C., cooling to the original 30 ° C. and exposing to ambient temperature, Broad Peak is still observed on DSC, which is water reabsorption. Can be caused by. Combining the XPRD results with the fact that form C can be obtained in a variety of aqueous systems, it was speculated that HCl salt form C is a hydrate (theoretical inclusion of monoHCl salt monohydrate). The amount of water was 3.4%). FIG. 28 shows DSC overlays of HCL form C before and after heating.
Unspecified form (DG)

See XRPD overlays in FIGS. 13A and 13B. HCl salt form D (812608-23-A2) was obtained by backsolvent addition to DCM / MeOH (good solvent) / DCM (reverse solvent), and the resulting clear solutions were first subjected to 5 ° C. and -20 ° C. And then evaporated at room temperature. 2.4% weight loss up to 150 ° C. and multiple endotherms were observed, as demonstrated by TGA and DSC data. The stoichiometric amount of acid / free base was determined by HPLC / IC to be 1.02.

To identify the HCl salt form D, readjustment was attempted by backsolvent addition to DCM / MeOH (good solvent) / DCM (backsolvent) followed by evaporation at room temperature. A mixture of HCl salt type C + D (812608-27-C) was obtained from the repreparation as determined by XRPD. A few special peaks are observed, which may be due to the new form or due to the relatively low crystallinity of the reference sample of HCl salt form D. TGA and DSC demonstrated weight loss of 4.8% in two steps up to 150 ° C., and multiple endothermic processes were observed. A sample containing a mixture of the HCl salt Form C + D is heated to 170 ° C. under N _2, cooled to 30 ° C., after exposure to ambient conditions, the mixture in the form A + C was observed (Figure 29). MeOH and limited DCM were not detected by NMR, so Form D is considered a hydrate.

13A and 13B again, HCl salt form E (812608-23-A5) are evaporated in THF _{/ H} 2 O (good solvent) / EtOH (antisolvent) antisolvent addition and subsequent of the room Was obtained from. As demonstrated by TGA and DSC, a weight loss of 13.5% up to 150 ° C. and two endothermic peaks at 105.8 ° C. and 273.6 ° C. (peak temperature) were observed. The stoichiometric amount of acid / free base was not determined due to the limited amount of sample.

To identify the HCl salt form E, readjustment _{was attempted by adding a back solvent to THF / H 2} O (good solvent) / EtOH (back solvent) followed by evaporation at room temperature. As determined by XRPD, a mixture of HCl salt form C + E (812608-27-D) was obtained from repreparation. A few special peaks were observed (emphasized), which may be due to the new form or due to the relatively low crystallinity of the reference sample of HCl salt form E. Two-step weight loss of 7.8% up to 150 ° C. and multiple thermal events were observed, as demonstrated by TGA and DSC. A sample containing a mixture of the HCl salt Form C + E is heated to 140 ° C. under N _2, cooled to 30 ° C., after being exposed to ambient temperature, the mixture in the form A + C was observed (Figure 30). Type E is considered a hydrate as THF and limited EtOH were not detected by NMR.

13A and 13B again, low crystallinity, new forms are _obtained from antisolvent addition and subsequent evaporation at room temperature to a _H 2 O / acetone (812608-23-A6), or HCl salt Form C (obtained by evaporation from 812608-23-A1, MeOH / H ₂ O) was obtained after exposure to ambient conditions (21 ± 1.5 ° C., 60 ± 20% RH) for 6 days. Is referred to as HCl salt form F. As demonstrated by TGA and DSC, a 7.3% weight loss up to 150 ° C. and two endothermic peaks at 120.6 and 274.7 ° C. (peak temperatures) were observed.

Finally, referring also to FIG. 13A and 13B and FIGS. 31, HCl salt form C (812608-21-A3, THF / H 2 was obtained by evaporation from O) is ambient temperature (21 ± 1.5 ℃, 60 After exposure to ± 20% RH) for 6 days, morphological changes were observed, which are referred to as HCl salt form G. As demonstrated by TGA and DSC, 8.9% weight loss up to 150 ° C. and multiple thermal events were observed for this form G.
result

Salt screening was performed on free base compound 2. A total of 12 salt hits were obtained from 33 salt screening experiments. Anhydrous HCl salt forms A and fumarate forms A were selected as precedents for salts for further evaluation, including hygroscopicity, kinetic solubility in various pH buffers, and stability in the solid state. As a result, both HCl salt form A and fumarate form A were slightly hygroscopic and showed good physicochemical stability under the conditions of 40 ° C./75% RH / week. Compared to free base form A, HCl form A showed increased solubility in buffers of pH 2, 5, and 7, but disproportionation and morphological changes were observed in buffers of pH 7.

Based on the characterization and evaluation results, anhydrous HCl salt form A was a preferred salt candidate and polymorphic screening was performed on the HCl salt (mono). Based on the XRPD comparison, in addition to anhydrous HCl salt form A, five new crystalline forms (hydrated HCl salt forms C and HCl salt forms D to G) were obtained from preliminary polymorph screening under 32 conditions. And new forms were characterized by TGA and DSC.

As a result of the preliminary salt screening of compound 2 and the polymorphic screening of the HCl salt (mono), the HCl salt form A is a preferred embodiment for development as an active pharmaceutical ingredient.
Equipment and methods for salt and polymorph screening Approximate solubility

^＊：５０℃で溶解した固形分
使用される溶媒の略称 The approximate solubility of free base form A (812608-05-A) was measured at room temperature in 12 solvents. For each experiment, approximately 2 mg of sample was added to a 3 mL glass vial. The solvents in Table 35 were then added stepwise (50, 50, 200, 200, 500 μL) to the vials until the solids were visibly dissolved or the total volume reached 1 mL. The solubility results summarized in Table 35 were used to guide solvent selection in salt screening.

^* : Solid content dissolved at 50 ° C Abbreviation for solvent used

機器および方法
ＸＲＰＤ Solvent abbreviations are listed in Table 36.

Equipment and methods XRPD

ＴＧＡおよびＤＳＣ For XRPD analysis, PANalytical X-ray powder diffraction in reflection mode was used. The XRPD parameters are listed in Table 37.

TGA and DSC

ＨＰＬＣ TGA data was collected using TA Q500 / Q5000 TGA from TA Instruments and DSCs were performed using TA Q200 / Q2000 DSC from TA Instruments. The detailed parameters used are listed in Table 38.

HPLC

^＊：試料８１２６０８−１２−Ａに関する動力学的溶解度試験および化学量論比に使用。
^＃：試料８１２６０８−０８−Ａ１／０８−Ｃ２／０８−Ａ３／０８−Ｂ４／１６−Ａ／２１−Ａ２／２３−Ａ２に関する化学量論比に使用。
イオンクロマトグラフィー Detailed chromatographic conditions for purity and solubility measurements utilizing Agent 1100/1260 HPLC are listed in Table 39.

^* : Used for kinetic solubility tests and stoichiometric ratios for sample 8126088-12-A.
^# : Used for stoichiometric ratios for sample 812608-08-A1 / 08-C2 / 08-A3 / 08-B4 / 16-A / 21-A2 / 23-A2.
Ion chromatography

動的蒸気収着 Table 40 lists the ion chromatography (IC) methods for measuring the counterion (anion) content that determine the chemical ratio.

Dynamic vapor sorption

溶液ＮＭＲ Dynamic vapor sorption (DVS) was measured via SMS (Surface Measurement System) DVS Intrisic. Relative humidity at 25 ° C. was calibrated for the deliquescent points of _{LiCl, Mg (NO 3} ) _{2, and KCl.} The actual parameters of the DVS test are listed in Table 41.

Solution NMR

Solution NMR was collected on a Bruker 400M NMR spectrometer using DMSO-d6.
Preparation procedure for pH buffer Preparation of stock solution

0.2M Hydrochloric Acid: 8.25 mL of concentrated hydrochloric acid is added to a 500 mL volumetric flask. Dilute the volume with purified water and mix well.

0.2M sodium hydroxide: Weigh 2.0 g of sodium hydroxide into a 250 mL volumetric flask. Dissolve this in an appropriate volume of purified water and dilute to volume. Mix well.

0.2M Potassium Chloride: 2.98 g of Potassium Chloride is weighed into a 200 mL volumetric flask. Dissolve this in an appropriate volume of purified water and dilute to volume. Mix well.

0.2M Potassium Dihydrogen Phosphate: Weigh 5.44 g of monobasic potassium dihydrogen phosphate (KH ₂ PO ₄ ) into a 200 mL volumetric flask. An appropriate volume of purified water is added and sonicated until all of the solids are completely dissolved. Dilute to volume with purified water and mix well.

0.2M Potassium Hydrogen phthalate Solution: _{Weigh 8.17 g of potassium hydrogen phthalate [KHC 6} H ₄ (COO) ₂ ] into a 200 mL volumetric flask. Add an appropriate volume of purified water and sonicate until all solids are completely dissolved. Dilute to volume with purified water and mix well.

pH 2.0 buffer: Transfer 25 mL of 0.2 M potassium chloride solution to a 100 mL volumetric flask and add 6.5 mL of 0.2 M hydrochloric acid solution. Sufficient purified water is added close to the target volume to adjust the pH to 2.0. Dilute to volume with purified water, mix well and check pH with a pH meter.

pH 5.0 buffer: Transfer 12.5 mL of 0.2 M potassium hydrogen phthalate solution and 5.6 mL of 0.2 M sodium hydroxide solution to a 50 mL volumetric flask. Sufficient purified water is added close to the target volume to adjust the pH to 5.0. Dilute to volume with purified water, mix well and check pH with a pH meter.

pH 7.0 buffer: Transfer 12.5 mL of 0.2 M potassium dihydrogen phosphate solution and 7.28 mL of 0.2 M sodium hydroxide solution to a 50 mL volumetric flask. Sufficient purified water is added close to the target volume to adjust the pH to 7.0. Dilute to volume with purified water, mix well and check pH with a pH meter.
(Example 10)
Predictive modeling of brain penetration

（実施例１１）
ビーグル犬における単一経口用量後の、化合物２の２種の懸濁製剤の、薬物動態および相対的バイオアベイラビリティー Compound 2 was evaluated for predictive properties that could allow compound entry through the blood-brain barrier (BBB). The multi-parameter score (“myMPO”) predicted BBB penetration taking into account physicochemical properties. Exercise was performed using a CNS drug as a comparative group. The higher the score (5 is ideal), the better the chance of CNS penetration. Various conclusions can be drawn from the movement, but one conclusion overlaps with the drug that goes down this list and still crosses the barrier very well to be effective. In particular, Table 42 provides an analysis for compound 2, see FIG. 32 for comparison groups. Thus, predictive modeling suggests that compound 2 is a noshinto but relatively weak.

(Example 11)
Pharmacokinetics and relative bioavailability of the two suspensions of Compound 2 after a single oral dose in Beagle dogs

The purpose of the study was to administer two suspensions of compound 2 at two dose levels to beagle dogs by forced feeding, and to collect blood samples to determine plasma concentrations and induce pharmacokinetic parameters. The relative bioavailability of the two suspensions is to be determined. The pharmacokinetics of compound 2 would be assessed after oral administration in capsules, determining the relative bioavailability of this dosage form for oral liquid formulations.

In this study, test items are administered by oral route over three periods with a 7-day washout period intervening, as outlined in Tables 43, 44, and 45. The third period of the study, outlined in Table 45, is considered as necessary and will only be conducted at the request of the sponsor. Before the dosing day, food is removed from the dog at 4:00 pm and reintroduced 2 hours after dosing.

For oral administration of the drug product, the test item was administered via the gastric tube, followed by administration of 10 mL of tap water. For oral administration of capsules, the capsules were placed on the back of the tongue to induce swallowing, followed by administration of 10 mL of tap water. The oral cavity was then examined to confirm that the capsule was swallowed. The actual volume of the administered dosing formulation is calculated based on the most recently listed body weight of the animal.

More specifically, male beagle dogs were orally administered with compound 2 as a solution in formulation # 1 (Table 43) and formulation # 2 (Table 44) at doses of 2 and 5 mg / kg, and these doses are well tolerated. However, there was mild vomiting in the only dog that received 5 mg / kg of Compound 2 in formulation # 2 (Table 44).

ＮＤ−終末期を定義するのに不適切な数の時点に起因して、決定されず
終末期に関する線形相関係数は、０．９８〜１．００に及んだ。ＡＵＣ_{０−Ｔｌａｓｔ}からＡＵＣ_０−∞への外挿は、１．８４〜１２．４８％に及んだ。
記述的統計を再計算して、データ用に提示されたフォーマットを製剤＃１（表４３）および＃２（表４４）と一致させた。 The pharmacokinetic parameters for compound 2 in solution as formulation # 1 (Table 43) and formulation # 2 (Table 44) are presented in Table 46, along with data on dosing of the powder of compound 2 in capsule (Table 45). ..

Due to an inadequate number of time points to define the ND-end of life, the linear correlation coefficient for the undetermined end of life ranged from 0.98 to 1.00. Extrapolation from the AUC _0-Tlast to AUC _0-∞ ranged from 1.84 to 12.48 percent.
The descriptive statistics were recalculated to match the format presented for the data with the formulations # 1 (Table 43) and # 2 (Table 44).

After oral administration of Compound 2 at doses of 2 and 5 mg / kg as solutions of Formula # 1 (Table 43) and Formulation # 2 (Table 44) and as powder in capsules (Table 45). , Plasma concentration of Compound 2 above the quantification limit (0.5 ng / mL) was observed in all dogs, and as a single representative species, it was observed by 0.5 hours after dosing.

_{At both doses, Tmax} values similar to formulation # 1 (Table 43), formulation # 2 (Table 44), and powder in capsules (Table 45) ranged from 3.0 to 4.7 hours. .. _{Average plasma half-life (t 1/2} ) for formulation # 1 (Table 43), formulation # 2 (Table 44), and powder in capsules (Table 45) at both doses, systemic clearance (CL / F) ), Volume of distribution (Vz / F), and average residence time are 2.3 to 5.6 hours, 20 to 33 L / kg / hr, 85 to 237 L / kg, and 5.23 to 9.32 hours, respectively. To.

For each formulation _{, increases in mean C max} and AUC _0-∞ were compared for dose increases from 2 mg / kg to 5 mg / kg (2.5 fold). Values for C _max and AUC _0-∞ are 4.1 and 4.0 for formulation # 1 (Table 43), 1.9 and 2.1 for formulation # 2 (Table 44), and powder in capsule, respectively. It was 1.7 and 1.8 with respect to (Table 45).

Plasma exposure to compound 2 at doses of 2 mg / kg and 5 mg / kg for formulation # 1 (Table 43), formulation # 2 (Table 44), and powder in capsule (Table 45), C _{max of} compound 2 and Comparisons were made by using both AUC _0-∞. Statistically significant difference between _{mean C max} and AUC _0-∞ values at each dose when comparing formulation # 1 (Table 43), formulation # 2 (Table 44), and powder in capsule (Table 45). Was not observed. However, fluctuating plasma concentrations were observed among the three dogs at each dose level and formulation.

The relative bioavailability of compound 2 may be compared for individual dogs based _{on C max} and AUC _0-∞ for product # 1 (Table 43) to product # 2 (Table 44), which are the same individual. This is because the dog receives both the product # 1 (Table 43) and the product # 2 (Table 44). At C _max and AUC _0-∞ , the mean relative bioavailability was 0.70 ± 0.26 and 0.78 ± 0.24 at a dose of 2 mg / kg, respectively, and 1 at a dose of 5 mg / kg. It was .22 ± 0.30 and 1.34 ± 0.06 (n = 3, ± SD).

In summary, the present disclosure is a study of oral dosing of Beagle dogs by oral forced feeding of Compound 2 prepared in Formula # 1 (Table 43), Formula # 2 (Table 44), and Powder in Capsules (Table 45). including. Compound 2 appears in plasma by 0.5 hours post-dose, with average C _max values of 6.78 to 14.90 ng / mL and 22.23 to 27.81 ng at doses of 2 and 5 mg / kg, respectively. Over / mL, mean T _max values range from 3.0 to 4.7 hours throughout both doses. Plasma half-life, clearance, volume of distribution, and mean residence time showed no apparent statistically significant differences across doses and formulations. But additional consideration can demonstrate unexpected benefits. Nonetheless, the data yielded a _{mean C max} and a mean AUC _0-∞ that exceeded the (synergistic) dose proportional increase for compound 2 of formulation # 1 (Table 43) as a result of the 2.5-fold dose increase. It is demonstrated that the values for formulation # 2 (Table 44) and powder in capsules (Table 45) are close to dose-proportional increase.

_{When comparing mean C max} , AUC0- _TLast , and AUC _0-∞ at doses of 2 and 5 mg / kg, formulation # 1 (Table 43), formulation # 2 (Table 44), and powder in capsule (Table 45). There was no significant difference between). Calculations of the relative bioavailability of compound 2 in product # 1 (Table 43) compared to product # 2 (Table 44) based on C _max and AUC _{0-∞ are at doses of 2 mg / kg, respectively.} The mean values of 0.70 and 0.78, as well as the mean values of 1.22 and 1.34 at a dose of 5 mg / kg were obtained.

Thus, although no direct correlation from dog-human pharmacokinetics is available, the results of a direct comparison of dog-dog pharmacokinetics after administration of the oral capsule formulation to the oral liquid formulation can be obtained. The results demonstrate that the bioavailability of the capsule formulation is similar to the two oral liquid formulations. As shown in FIGS. 33A and 33B, the plasma concentration of compound 2 in the species tested is comparable between the powder formulation (Table 45) and the liquid formulation (Table 43). Plasma half-life, clearance, volume of distribution, and mean residence time showed no substantial differences across doses and formulations.

の化合物またはその結晶塩を投与することを含む、方法。
実施形態２． 前記結晶塩が、酸付加塩である、実施形態１に記載の方法。
実施形態３． 前記酸付加塩が、塩酸塩である、実施形態２に記載の方法。
実施形態４． 前記塩酸塩が、１価である、実施形態３に記載の方法。
実施形態５． 結晶塩形態が、無水物である、実施形態１から４のいずれか１つに記載の方法。
実施形態６． 前記対象が、小児患者である、実施形態１から５のいずれか１つに記載の方法。
実施形態７． 前記対象が、約１週齢から約２２歳である、実施形態１から５のいずれか１つに記載の方法。
実施形態８． 前記対象が、約１８歳またはそれよりも若い、実施形態１から７のいずれか１つに記載の方法。
実施形態９． 前記対象が、約１０歳またはそれよりも若い、実施形態１から８のいずれか１つに記載の方法。
実施形態１０． 前記対象が、約８歳またはそれよりも若い、実施形態１から９のいずれか１つに記載の方法。
実施形態１１． 前記対象が、約６歳またはそれよりも若い、実施形態１から１０のいずれか１つに記載の方法。
実施形態１２． 前記ＤＩＰＧが、新たに診断されたものまたは再発である、実施形態１から１１のいずれか１つに記載の方法。
実施形態１３． 前記ＤＩＰＧが、浸潤性グリオーマ グレードＩＩからＩＶと組織学的診断がなされた脳橋腫瘍として特徴付けられる、実施形態１から１２のいずれか１つに記載の方法。
実施形態１４． 放射線療法を投与することをさらに含む、実施形態１から１３のいずれか１つに記載の方法。
実施形態１５． 放射線の投与が、前記化合物またはその結晶塩の投与の前に行われる、実施形態１４に記載の方法。
実施形態１６． 放射線の投与が、前記化合物またはその結晶塩の投与の後に行われる、実施形態１５に記載の方法。
実施形態１７． 放射線の投与が、前記化合物またはその結晶塩の投与の前および後の両方で行われる、実施形態１６に記載の方法。
実施形態１８． １種またはそれより多種の追加の治療剤を投与することをさらに含む、実施形態１から１７のいずれか１つに記載の方法。
実施形態１９． 前記化合物またはその結晶塩の投与が、ＤＩＰＧに関連する１つまたはそれより多くの徴候または症状を低減させまたは軽減させる、実施形態１から１８のいずれか１つに記載の方法。
実施形態２０． 前記１つまたはそれより多くの徴候または症状が、会話または会話パターンの変容、対象の顔または身体の片側を動かす能力の損失、バランスの損失、協調の損失、歩行または運動に関するトラブル、視覚の問題、聴覚の問題、頭痛、吐き気、嘔吐、異常な眠気、エネルギーレベルの変容、行動変化、および学校での成績の変化からなる群から選択される、実施形態１９に記載の方法。
実施形態２１． 前記化合物またはその結晶塩の投与が、無憎悪生存期間を実現する、実施形態１から２０のいずれか１つに記載の方法。
実施形態２２． 前記無憎悪生存期間が、１か月もしくはそれよりも長い、２か月もしくはそれよりも長い、３か月もしくはそれよりも長い、４か月もしくはそれよりも長い、５か月もしくはそれよりも長い、６か月もしくはそれよりも長い、７か月もしくはそれよりも長い、８か月もしくはそれよりも長い、９か月もしくはそれよりも長い、１０か月もしくはそれよりも長い、１１か月もしくはそれよりも長い、１年もしくはそれよりも長い、２年もしくはそれよりも長い、３年もしくはそれよりも長い、または５年もしくはそれよりも長い、実施形態２１に記載の方法。
実施形態２３． 腫瘍成長の減量術または脳脊髄液転換の１つまたは複数をさらに含む、実施形態１から２２のいずれか１つに記載の方法。
実施形態２４． 前記対象が、ＡＣＶＲ１遺伝子中に１つまたはそれより多くの変異を含む所定の遺伝子プロファイルを有する、実施形態１から２３のいずれか１つに記載の方法。
実施形態２５． ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、活性化変異である、実施形態２４に記載の方法。
実施形態２６． 前記ＡＣＶＲ１遺伝子中の１つまたはそれより多くの変異が、Ｒ２０６Ｈ、Ｇ３２８Ｖ、Ｒ２５８Ｇ、またはこれらの組合せから選択される、１つまたはそれより多くのアミノ酸残基におけるアミノ酸置換を含むＡＣＶＲ１ポリペプチドをコードする、実施形態２５に記載の方法。
実施形態２７． 前記ＡＣＶＲ１ポリペプチド中のアミノ酸置換がＲ２０６Ｈを含む、実施形態２６に記載の方法。
実施形態２８． 前記化合物またはその結晶塩が経口投与される、実施形態１から２７のいずれか１つに記載の方法。
実施形態２９． 前記化合物またはその結晶塩が、週当たり約１０ｍｇから約３２０ｍｇに及ぶ用量で投与される、実施形態１から２８のいずれか１つに記載の方法。
実施形態３０． 前記用量が、週当たり約３０ｍｇから約２４０ｍｇに及ぶ、実施形態２９に記載の方法。
実施形態３１． 前記用量が、週当たり約６０ｍｇから約１８０ｍｇに及ぶ、実施形態２９に記載の方法。
実施形態３２． 前記用量が、週当たり約３０ｍｇから約１２０ｍｇに及ぶ、実施形態２９に記載の方法。
実施形態３３． 前記用量が、週当たり約６０ｍｇから約１２０ｍｇに及ぶ、実施形態２９に記載の方法。
実施形態３４． 前記用量が、週当たり約６０ｍｇである、実施形態２９に記載の方法。
実施形態３５． 前記用量が、週当たり約９０ｍｇである、実施形態２９に記載の方法。
実施形態３６． 前記用量が、週当たり約１２０ｍｇである、実施形態２９に記載の方法。
実施形態３７． 前記用量が、週当たり約１８０ｍｇである、実施形態２９に記載の方法。
実施形態３８． 前記用量が、週当たり約２１０ｍｇである、実施形態２９に記載の方法。
実施形態３９． 前記用量が、週当たり約２４０ｍｇである、実施形態２９に記載の方法。
実施形態４０． 前記化合物またはその結晶塩が、約３２０ｍｇもしくはそれよりも少ない、約２４０ｍｇもしくはそれよりも少ない、約２１０もしくはそれよりも少ない、約１８０もしくはそれよりも少ない、約１２０もしくはそれよりも少ない、約９０もしくはそれよりも少ない、約６０もしくはそれよりも少ない、または約３０もしくはそれよりも少ない１週用量で投与される、実施形態１から２８のいずれか１つに記載の方法。
実施形態４１． 前記用量が、週当たり約６０ｍｇまたはそれよりも少ない、実施形態４０に記載の方法。
実施形態４２． 前記用量が、週当たり約９０ｍｇまたはそれよりも少ない、実施形態４０に記載の方法。
実施形態４３． 前記用量が、週当たり約１２０ｍｇまたはそれよりも少ない、実施形態４０に記載の方法。
実施形態４４． 前記用量が、週当たり約１８０ｍｇまたはそれよりも少ない、実施形態４０に記載の方法。
実施形態４５． 前記用量が、週当たり約２１０ｍｇまたはそれよりも少ない、実施形態４０に記載の方法。
実施形態４６． 前記用量が、週当たり約２４０ｍｇまたはそれよりも少ない、実施形態４０に記載の方法。
実施形態４７． 前記用量が、週に１回投与される、実施形態２９から４６のいずれか１つに記載の方法。
実施形態４８． 前記用量が、１週間のクールにわたって２回またはそれを超える回数の部分用量、３回またはそれを超える回数の部分用量、４回またはそれを超える回数の部分用量、５回またはそれを超える回数の部分用量、６回またはそれを超える回数の部分用量、または毎日の部分用量で投与される、実施形態２９から４６のいずれか１つに記載の方法。
実施形態４９． 前記対象が小児患者であり、前記用量が、前記用量範囲の約８０％から１００％の間である、実施形態２９から４８のいずれか１つに記載の方法。
実施形態５０． 前記用量が、前記用量範囲の約８０％、８５％、９０％、または９５％に調節される、実施形態４９に記載の方法。
実施形態５１． 前記用量が、週当たり約８ｍｇから約３２０ｍｇに及ぶ、実施形態４９に記載の方法。
実施形態５２． 前記用量が、週当たり約２４ｍｇから約２４０ｍｇに及ぶ、実施形態４９に記載の方法。
実施形態５３． 前記用量が、週当たり約２４ｍｇから約１２０ｍｇに及ぶ、実施形態４９に記載の方法。
実施形態５４． 前記用量が、週当たり約４８ｍｇから約１２０ｍｇに及ぶ、実施形態４９に記載の方法。
実施形態５５． 前記用量が、週当たり約７２ｍｇから約１２０ｍｇに及ぶ、実施形態４９に記載の方法。
実施形態５６． 前記用量が、週当たり約９６ｍｇから約１２０ｍｇに及ぶ、実施形態４９に記載の方法。
実施形態５７． 前記対象が、少なくとも約０．１ｎｇ／ｍＬの所定のヘプシジンレベルを有する、実施形態１から５６のいずれか１つに記載の方法。
実施形態５８． 前記所定のヘプシジンレベルが、約１０ｎｇ／ｍＬから約２００ｎｇ／ｍＬに及ぶ、実施形態５７に記載の方法。
実施形態５９． 前記化合物またはその結晶塩が投与された後に、前記対象のヘプシジンレベルを決定することをさらに含む、実施形態１から５８のいずれか１つに記載の方法。
実施形態６０． 前記化合物またはその結晶塩が投与された後に、前記対象のトランスフェリン飽和レベルを決定することをさらに含む、実施形態１から５９のいずれか１つに記載の方法。
実施形態６１． 前記トランスフェリン飽和レベルが、約５０％未満である、実施形態６０に記載の方法。
実施形態６２． 前記トランスフェリン飽和レベルが、約４５％未満である、実施形態６０に記載の方法。
実施形態６３． 前記トランスフェリン飽和レベルが、約４０％未満である、実施形態６０に記載の方法。
実施形態６４． 前記化合物またはその結晶塩が、１回またはそれを超える回数の処置サイクルにわたり投与され、各サイクルが４週を含む、実施形態１から６３のいずれか１つに記載の方法。
実施形態６５． 前記方法が、処置サイクル間に１日またはそれを超える日数の休処置日をさらに含む、実施形態６４に記載の方法。
実施形態６６． 前記休処置日が、１日、２日、３日、４日、５日、６日、１週、２週、３週、または４週から選択される、実施形態６５に記載の方法。
実施形態６７． ＡＣＶＲ１の阻害の影響を受け易い疾患または障害を処置するための方法であって、前記方法は、ＡＣＶＲ１の阻害の影響を受け易い疾患または障害の処置を必要とする対象に、治療有効量の式（２）：

の化合物またはその結晶塩を投与することを含み、前記化合物が、週当たり約１０ｍｇから約３２０ｍｇに及ぶ用量で投与される、方法。
実施形態６８． 前記用量が、週当たり約３０ｍｇから約２４０ｍｇに及ぶ、実施形態６７に記載の方法。
実施形態６９． 前記用量が、週当たり約６０ｍｇから約１８０ｍｇに及ぶ、実施形態６７に記載の方法。
実施形態７０． 前記用量が、週当たり約３０ｍｇから約１２０ｍｇに及ぶ、実施形態６７に記載の方法。
実施形態７１． 前記用量が、週当たり約６０ｍｇから約１２０ｍｇに及ぶ、実施形態６７に記載の方法。
実施形態７２． 前記用量が、週当たり約６０ｍｇである、実施形態６７に記載の方法。
実施形態７３． 前記用量が、週当たり約９０ｍｇである、実施形態６７に記載の方法。
実施形態７４． 前記用量が、週当たり約１２０ｍｇである、実施形態６７に記載の方法。
実施形態７５． 前記用量が、週当たり約１８０ｍｇである、実施形態６７に記載の方法。
実施形態７６． 前記用量が、週当たり約２１０ｍｇである、実施形態６７に記載の方法。
実施形態７７． 前記用量が、週当たり約２４０ｍｇである、実施形態６７に記載の方法。
実施形態７８． 前記化合物またはその結晶塩が、約３２０ｍｇもしくはそれよりも少ない、約２４０ｍｇもしくはそれよりも少ない、約２１０もしくはそれよりも少ない、約１８０もしくはそれよりも少ない、約１２０もしくはそれよりも少ない、約９０もしくはそれよりも少ない、約６０もしくはそれよりも少ない、または約３０もしくはそれよりも少ない１週用量で投与される、実施形態６７から７７のいずれか１つに記載の方法。
実施形態７９． 前記用量が、週当たり約６０ｍｇまたはそれよりも少ない、実施形態７８に記載の方法。
実施形態８０． 前記用量が、週当たり約９０ｍｇまたはそれよりも少ない、実施形態７８に記載の方法。
実施形態８１． 前記用量が、週当たり約１２０ｍｇまたはそれよりも少ない、実施形態７８に記載の方法。
実施形態８２． 前記用量が、週当たり約１８０ｍｇまたはそれよりも少ない、実施形態７８に記載の方法。
実施形態８３． 前記用量が、週当たり約２１０ｍｇまたはそれよりも少ない、実施形態７８に記載の方法。
実施形態８４． 前記用量が、週当たり約２４０ｍｇまたはそれよりも少ない、実施形態７８に記載の方法。
実施形態８５． 前記対象が小児患者であり、前記用量が、前記用量範囲の約８０％から１００％の間である、実施形態６７から８４のいずれか１つに記載の方法。
実施形態８６． 前記用量が、前記用量範囲の約８０％、８５％、９０％、または９５％である、実施形態８５に記載の方法。
実施形態８７． 前記用量が、週当たり約８ｍｇから約３２０ｍｇに及ぶ、実施形態８５に記載の方法。
実施形態８８． 前記用量が、週当たり約２４ｍｇから約２４０ｍｇに及ぶ、実施形態８５に記載の方法。
実施形態８９． 前記用量が、週当たり約２４ｍｇから約１２０ｍｇに及ぶ、実施形態８５に記載の方法。
実施形態９０． 前記用量が、週当たり約４８ｍｇから約１２０ｍｇに及ぶ、実施形態８５に記載の方法。
実施形態９１． 前記用量が、週当たり約７２ｍｇから約１２０ｍｇに及ぶ、実施形態８５に記載の方法。
実施形態９２． 前記用量が、週当たり約９６ｍｇから約１２０ｍｇに及ぶ、実施形態８５に記載の方法。
実施形態９３． 前記用量が、１週間に１回投与される、実施形態６７から９２のいずれか１つに記載の方法。
実施形態９４． 前記用量が、１週間のクールにわたって２回の部分用量で投与される、実施形態６７から９２のいずれか１つに記載の方法。
実施形態９５． 前記用量が、１週間のクールにわたって３回の部分用量で投与される、実施形態６７から９２のいずれか１つに記載の方法。
実施形態９６． 前記用量が、１週間のクールにわたって４回の部分用量で投与される、実施形態６７から９２のいずれか１つに記載の方法。
実施形態９７． 前記用量が、１週間のクールにわたって５回の部分用量で投与される、実施形態６７から９２のいずれか１つに記載の方法。
実施形態９８． 前記用量が、１週間のクールにわたって６回の部分用量で投与される、実施形態６７から９２のいずれか１つに記載の方法。
実施形態９９． 前記用量が、毎日の部分用量で投与される、実施形態６７から９２のいずれか１つに記載の方法。
実施形態１００． 前記対象が、ＡＣＶＲ１遺伝子中に１つまたはそれより多くの変異を含む所定の遺伝子プロファイルを有する、実施形態６７から９９のいずれか１つに記載の方法。
実施形態１０１． ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、活性化変異である、実施形態１００に記載の方法。
実施形態１０２． 前記ＡＣＶＲ１遺伝子中の１つまたはそれより多くの変異が、Ｒ２０６Ｈ、Ｇ３２８Ｖ、Ｒ２５８Ｇ、またはこれらの組合せから選択される、１つまたはそれより多くのアミノ酸残基におけるアミノ酸置換を含むＡＣＶＲ１ポリペプチドをコードする、実施形態１０１に記載の方法。
実施形態１０３． 前記ＡＣＶＲ１ポリペプチド中のアミノ酸置換が、Ｒ２０６Ｈを含む、実施形態１０２に記載の方法。
実施形態１０４． 前記化合物またはその結晶塩が、経口投与される、実施形態６７から１０３のいずれか１つに記載の方法。
実施形態１０５． 前記疾患または障害が、びまん性真性橋膠腫、グレードＩＩからＩＶの浸潤性グリオーマと組織学的診断がなされた脳橋腫瘍、固形腫瘍、進行性骨化性線維異形成症、および慢性疾患の貧血症の１つまたは複数から選択される、実施形態６７から１０４のいずれか１つに記載の方法。
実施形態１０６． 前記化合物またはその結晶塩が、固体用量製剤として投与される、実施形態１０５に記載の方法。
実施形態１０７． 前記化合物またはその結晶塩が、液体用量製剤として投与される、実施形態１０５に記載の方法。
実施形態１０８． 前記対象が、用量の任意の修正を決定するためにヘプシジンレベルに関してモニタリングされる、実施形態６７から１０７のいずれか１つに記載の方法。
実施形態１０９． 前記対象が、１つまたはそれより多くの臓器における前記化合物の蓄積に関してモニタリングされる、実施形態６７から１０８のいずれか１つに記載の方法。
実施形態１１０． 前記結晶塩が、酸付加塩である、実施形態６７から１０９のいずれか１つに記載の方法。
実施形態１１１． 前記酸付加塩が、塩酸塩である、実施形態１１０に記載の方法。
実施形態１１２． 前記塩酸塩が、１価である、実施形態１１１に記載の方法。
実施形態１１３． 前記結晶塩形態が、無水物である、実施形態１１０から１１２のいずれか１つに記載の方法。
実施形態１１４． １種またはそれより多種の薬学的に許容される賦形剤と、式（２）：

の化合物またはその結晶塩とを含む経口固体医薬組成物であって、前記化合物が、遊離塩基重量に対して約５ｍｇから約１２５ｍｇの間の力価で製剤化される、医薬組成物。
実施形態１１５． 前記結晶塩が、酸付加塩である、実施形態１１４に記載の医薬組成物。
実施形態１１６． 前記酸付加塩が、塩酸塩である、実施形態１１５に記載の医薬組成物。
実施形態１１７． 前記塩酸塩が、１価である、実施形態１１６に記載の医薬組成物。
実施形態１１８． 前記結晶塩形態が、無水物である、実施形態１１５から１１７のいずれか１つに記載の医薬組成物。
実施形態１１９． 前記医薬組成物が、ゼラチンカプセルである、実施形態１１４から１１８のいずれか１つに記載の医薬組成物。
実施形態１２０． 前記ゼラチンカプセルが、遊離塩基重量に対して（ｉ）５ｍｇ、（ｉｉ）２５ｍｇ、または（ｉｉｉ）１２５ｍｇの力価である、実施形態１１９に記載の医薬組成物。
実施形態１２１． 前記ゼラチンカプセルが、遊離塩基重量に対して（ｉ）３０ｍｇ、（ｉｉ）６０ｍｇ、（ｉｉｉ）９０ｍｇ、または（ｉｖ）１２０ｍｇである、実施形態１１９に記載の医薬組成物。
実施形態１２２． 前記１種またはそれより多種の医薬賦形剤が、微結晶性セルロース、ラクトース一水和物、クロスカルメロースナトリウム、ステアリン酸マグネシウム、またはこれらの組合せから選択される、実施形態１１４から１２１のいずれか１つに記載の医薬組成物。
実施形態１２３． 式（２）：

の化合物またはその結晶塩と；
（ｉ）１種またはそれより多種の緩衝剤；
（ｉｉ）必要に応じて、１種またはそれより多種の保存剤；
（ｉｉｉ）必要に応じて、１種またはそれより多種の溶媒；
（ｉｖ）必要に応じて、１種またはそれより多種の矯味剤；および
（ｖ）必要に応じて、１種またはそれより多種のさらなるｐＨ調節剤
とを含む、経口液体医薬組成物。
実施形態１２４． 前記結晶塩が、酸付加塩である、実施形態１２３に記載の医薬組成物。
実施形態１２５． 前記酸付加塩が、塩酸塩である、実施形態１２４に記載の医薬組成物。
実施形態１２６． 前記塩酸塩が、１価である、実施形態１２５に記載の医薬組成物。
実施形態１２７． 前記結晶塩形態が、無水物である、実施形態１２４から１２６のいずれか１つに記載の医薬組成物。
実施形態１２８． 前記組成物が約２．０から約５．０の間のｐＨを有する、実施形態１２３から１２７のいずれか１つに記載の医薬組成物。
実施形態１２９． 前記組成物が約２．０から約３．５の間のｐＨを有する、実施形態１２８に記載の医薬組成物。
実施形態１３０． 前記組成物が約２．０のｐＨを有する、実施形態１２８に記載の医薬組成物。
実施形態１３１． 前記緩衝剤が、クエン酸、酒石酸、リンゴ酸、または酢酸から選択される、実施形態１２３から１３０のいずれか１つに記載の医薬組成物。
実施形態１３２． 前記緩衝剤が、リンゴ酸である、実施形態１３１に記載の医薬組成物。
実施形態１３３． 前記リンゴ酸が、ＤＬ−リンゴ酸である、実施形態１３２に記載の医薬組成物。
実施形態１３４． １種またはそれより多種の保存剤を含む、実施形態１２３から１３３のいずれか１つに記載の医薬組成物。
実施形態１３５． 前記保存剤が、安息香酸、安息香酸ナトリウム、パラヒドロキシ安息香酸メチル、パラヒドロキシ安息香酸プロピル、またはプロピレングリコールから選択される、実施形態１３４に記載の医薬組成物。
実施形態１３６． 前記保存剤が、安息香酸である、実施形態１３５に記載の医薬組成物。
実施形態１３７． 前記安息香酸が、保存剤および緩衝剤である、実施形態１３６に記載の医薬組成物。
実施形態１３８． １種またはそれより多種の矯味剤を含む、実施形態１２３から１３７のいずれか１つに記載の医薬組成物。
実施形態１３９． 前記矯味剤が、スクラロース、グリセリン、シクロデキストリン、ＨＰ−β−シクロデキストリン、α−シクロデキストリン、β−シクロデキストリン、またはこれらの組合せから選択される、実施形態１３８に記載の医薬組成物。
実施形態１４０． 前記矯味剤が、ＨＰ−β−シクロデキストリンおよびスクラロースの組合せである、実施形態１３８に記載の医薬組成物。
実施形態１４１． 前記組成物が、式（２）の化合物またはその結晶塩を、約１０ｍｇ／ｍＬの濃度で含む、実施形態１２３から１４０のいずれか１つに記載の医薬組成物。
実施形態１４２． 前記組成物が、リンゴ酸を約６．７ｍｇ／ｍＬまでの濃度で含む、実施形態１２３から１４１のいずれか１つに記載の医薬組成物。
実施形態１４３． 前記組成物が、リンゴ酸を約１．３ｍｇ／ｍＬの濃度で含む、実施形態１４２に記載の医薬組成物。
実施形態１４４． 前記組成物が、ＨＰ−β−シクロデキストリンを約３００ｍｇ／ｍＬまでの濃度で含む、実施形態１２３から１４３のいずれか１つに記載の医薬組成物。
実施形態１４５． 前記組成物が、ＨＰ−β−シクロデキストリンを約１５０ｍｇ／ｍＬまでの濃度で含む、実施形態１４４に記載の医薬組成物。
実施形態１４６． 前記組成物が、スクラロースを約２．０ｍｇ／ｍＬまでの濃度で含む、実施形態１２３から１４５のいずれか１つに記載の医薬組成物。
実施形態１４７． 前記組成物が、スクラロースを約１．０ｍｇ／ｍＬの濃度で含む、実施形態１４６に記載の医薬組成物。
実施形態１４８． 前記組成物が、安息香酸を約３．０ｍｇ／ｍＬまでの濃度で含む、実施形態１２３から１４７のいずれか１つに記載の医薬組成物。
実施形態１４９． 前記組成物が、安息香酸を約２．０ｍｇ／ｍＬまでの濃度で含む、実施形態１４８に記載の医薬組成物。
実施形態１５０． 前記ｐＨが、塩酸で約２．０に調節される、実施形態１２３から１４９のいずれか１つに記載の医薬組成物。
実施形態１５１． 前記溶媒が水である、実施形態１２３から１５０のいずれか１つに記載の医薬組成物。
実施形態１５２． 化合物（２）

Ｎ^４−（２，２’−ビピリジン−３−イル）−Ｎ^２−（３−メトキシ−４−（４−メチルピペラジン−１−イル）フェニル）ピリミジン−２，４−ジアミンの塩の結晶形態。
実施形態１５３． 前記塩が、薬学的に許容される塩である、実施形態１５２に記載の結晶形態。
実施形態１５４． 前記薬学的に許容される塩が、ＨＣｌ塩である、実施形態１５３に記載の結晶形態。
実施形態１５５． 形態Ａを含む、実施形態１５２から１５４のいずれか１つに記載の結晶形態。
実施形態１５６． 前記形態Ａから本質的になる、実施形態１５２から１５４のいずれか１つに記載の結晶形態。
実施形態１５７． 形態Ａが、不純物を実質的に含まない、実施形態１５５または１５６に記載の結晶形態。
実施形態１５８． Ｎ^４−（２，２’−ビピリジン−３−イル）−Ｎ^２−（３−メトキシ−４−（４−メチルピペラジン−１−イル）フェニル）ピリミジン−２，４−ジアミン無水塩酸塩の、化合物形態Ａ。
実施形態１５９． １３．５３、１６．１４、１７．６７、１８．３８、２４．９６、および２８．１８から選択される１つまたは複数の２θ値を含むｘ線回折パターン（ＸＲＰＤ）を特徴とする、Ｎ^４−（２，２’−ビピリジン−３−イル）−Ｎ^２−（３−メトキシ−４−（４−メチルピペラジン−１−イル）フェニル）ピリミジン−２，４−ジアミン無水塩酸塩の化合物形態Ａ。
実施形態１６０． 前記形態が、列挙される２θ値のうちの２つまたはそれよりも多くを特徴とする、実施形態１５９に記載の形態Ａ。
実施形態１６１． 前記形態が、列挙される２θ値のうちの３つまたはそれよりも多くを特徴とする、実施形態１５９に記載の形態Ａ。
実施形態１６２． 前記形態が、列挙される２θ値のうちの４つまたはそれよりも多くを特徴とする、実施形態１５９に記載の形態Ａ。
実施形態１６３． 前記形態が、列挙される２θ値のうちの５つまたはそれよりも多くを特徴とする、実施形態１５９に記載の形態Ａ。
実施形態１６４． 前記形態が、列挙される２θ値の６つ全てを特徴とする、実施形態１５９に記載の形態Ａ。
実施形態１６５． ６．７１、１９．２５、２３．９８、および２９．６０から選択される１つまたは複数の２θ値をさらに特徴とする、実施形態１５７から１６４のいずれか１つに記載の形態Ａ。
実施形態１６６． 前記形態が、列挙される２θ値のうちの２つまたはそれよりも多くを特徴とする、実施形態１６５に記載の形態Ａ。
実施形態１６７． 前記形態が、列挙される２θ値のうちの３つまたはそれよりも多くを特徴とする、実施形態１６５に記載の形態Ａ。
実施形態１６８． 前記形態が、列挙される２θ値のうちの４つ全てを特徴とする、実施形態１６５に記載の形態Ａ。
実施形態１６９． 前記Ｘ線粉末回折計が、Ｃｕ ｋαのＸ線波長、Ｋα１（Å）：１．５４０５９８、Ｋα２（Å）：１．５４４４２６を使用して、Ｋα２／Ｋα１強度比を０．５０、そしてＸ線管の設定を４５ｋＶ、４０ｍＡにして反射モードで使用される、実施形態１５８から１６８のいずれか１つに記載の形態Ａ。
実施形態１７０． 前記２θ値が、±０．２ ２θ以内である、実施形態１５８から１６９のいずれか１つに記載の形態Ａ。
実施形態１７１． 図１２と実質的に同じｘ線回折パターン（ＸＲＰＤ）を特徴とする、Ｎ^４−（２，２’−ビピリジン−３−イル）−Ｎ^２−（３−メトキシ−４−（４−メチルピペラジン−１−イル）フェニル）ピリミジン−２，４−ジアミン無水塩酸塩の化合物形態Ａ。
実施形態１７２． １９６．２℃、２１４．８℃、および２７４．０℃のうちの１つまたは複数での吸熱を特徴とする、Ｎ^４−（２，２’−ビピリジン−３−イル）−Ｎ^２−（３−メトキシ−４−（４−メチルピペラジン−１−イル）フェニル）ピリミジン−２，４−ジアミン無水塩酸塩の化合物形態Ａ。
実施形態１７３． １９８．９℃、２１８．０℃、および２７５．９℃のうちの１つまたは複数でのピーク吸熱をさらに特徴とする、実施形態１７２に記載の形態Ａ。
実施形態１７４． ２７４．０℃の開始温度をさらに特徴とする、実施形態１７２または１７３に記載の形態Ａ。
実施形態１７５． １５０℃までで１．７％の重量損失をさらに特徴とする、実施形態１７２から１７４のいずれか１つに記載の形態Ａ。
実施形態１７６． 図１５と実質的に同じＴＧＡ−ＤＳＣサーモグラムを特徴とする、Ｎ^４−（２，２’−ビピリジン−３−イル）−Ｎ^２−（３−メトキシ−４−（４−メチルピペラジン−１−イル）フェニル）ピリミジン−２，４−ジアミン無水塩酸塩の化合物形態Ａ。
実施形態１７７． 実施形態１５２から１７６のいずれか１つに記載の結晶形態を含む医薬組成物。
実施形態１７８． 固体用量製剤としての、実施形態１７６に記載の医薬組成物。
実施形態１７９． 前記化合物が、実施形態１５２から１７６のいずれか１つに記載の結晶形態である、実施形態１１４から１２２のいずれか１つに記載の経口固体医薬組成物。
実施形態１８０． 液体用量製剤としての、実施形態１７６に記載の医薬組成物。
実施形態１８１． 前記化合物が、実施形態１５２から１７６のいずれか１つに記載の結晶形態である、実施形態１２３から１５１のいずれか１つに記載の経口液体医薬組成物。
実施形態１８２． 前記化合物が、実施形態１５２から１７６のいずれか１つに記載の結晶形態である、実施形態１から１１３のいずれか１つに記載の方法。 Embodiments and embodiments:
Embodiments and embodiments of the present disclosure that may be included in various combinations include:
Embodiment 1. A method of treating diffuse true pontine glioma (DIPG) in a subject requiring treatment of diffuse true pontine glioma (DIPG), wherein the method is a therapeutically effective amount of equation (2) :.

A method comprising administering a compound of, or a crystalline salt thereof.
Embodiment 2. The method according to the first embodiment, wherein the crystalline salt is an acid addition salt.
Embodiment 3. The method according to embodiment 2, wherein the acid addition salt is a hydrochloride.
Embodiment 4. The method according to embodiment 3, wherein the hydrochloride salt is monovalent.
Embodiment 5. The method according to any one of embodiments 1 to 4, wherein the crystalline salt form is anhydrous.
Embodiment 6. The method according to any one of embodiments 1 to 5, wherein the subject is a pediatric patient.
Embodiment 7. The method according to any one of embodiments 1 to 5, wherein the subject is about 1 week to about 22 years old.
Embodiment 8. The method according to any one of embodiments 1 to 7, wherein the subject is about 18 years old or younger.
Embodiment 9. The method according to any one of embodiments 1 to 8, wherein the subject is about 10 years or younger.
Embodiment 10. The method according to any one of embodiments 1 to 9, wherein the subject is about 8 years or younger.
Embodiment 11. The method according to any one of embodiments 1 to 10, wherein the subject is about 6 years or younger.
Embodiment 12. The method according to any one of embodiments 1 to 11, wherein the DIPG is newly diagnosed or recurrent.
Embodiment 13. The method according to any one of embodiments 1-12, wherein the DIPG is characterized as a pontine tumor histologically diagnosed as invasive glioma grade II to IV.
Embodiment 14. The method according to any one of embodiments 1 to 13, further comprising administering radiation therapy.
Embodiment 15. 13. The method of embodiment 14, wherein the administration of radiation is performed prior to administration of the compound or a crystalline salt thereof.
Embodiment 16. 15. The method of embodiment 15, wherein the administration of radiation is performed after administration of the compound or a crystalline salt thereof.
Embodiment 17. 16. The method of embodiment 16, wherein the administration of radiation is performed both before and after administration of the compound or a crystalline salt thereof.
Embodiment 18. The method according to any one of embodiments 1 to 17, further comprising administering one or more additional therapeutic agents.
Embodiment 19. The method of any one of embodiments 1-18, wherein administration of the compound or crystalline salt thereof reduces or alleviates one or more signs or symptoms associated with DIPG.
20. One or more of the above symptoms or symptoms may be changes in conversation or conversation patterns, loss of ability to move one side of the subject's face or body, loss of balance, loss of coordination, walking or motor problems, visual problems. 19. The method of embodiment 19, wherein the method is selected from the group consisting of hearing problems, headache, nausea, vomiting, abnormal drowsiness, altered energy levels, behavioral changes, and altered school performance.
21. The method according to any one of embodiments 1 to 20, wherein administration of the compound or a crystalline salt thereof achieves a hate-free survival time.
Embodiment 22. The hateless survival time is one month or longer, two months or longer, three months or longer, four months or longer, five months or longer. Long, 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, 10 months or longer, 11 months 21. The method of embodiment 21, which is longer than that, one year or longer, two years or longer, three years or longer, or five years or longer.
23. The method according to any one of embodiments 1 to 22, further comprising one or more of tumor growth weight loss surgery or cerebrospinal fluid conversion.
Embodiment 24. The method according to any one of embodiments 1 to 23, wherein the subject has a predetermined gene profile that comprises one or more mutations in the ACVR1 gene.
Embodiment 25. The method of embodiment 24, wherein the one or more mutations in the ACVR1 gene are activating mutations.
Embodiment 26. One or more mutations in the ACVR1 gene encode an ACVR1 polypeptide containing amino acid substitutions at one or more amino acid residues selected from R206H, G328V, R258G, or a combination thereof. 25. The method according to embodiment 25.
Embodiment 27. 26. The method of embodiment 26, wherein the amino acid substitution in the ACVR1 polypeptide comprises R206H.
Embodiment 28. The method according to any one of embodiments 1 to 27, wherein the compound or a crystalline salt thereof is orally administered.
Embodiment 29. The method of any one of embodiments 1-28, wherein the compound or crystalline salt thereof is administered at a dose ranging from about 10 mg to about 320 mg per week.
Embodiment 30. 29. The method of embodiment 29, wherein the dose ranges from about 30 mg to about 240 mg per week.
Embodiment 31. 29. The method of embodiment 29, wherein the dose ranges from about 60 mg to about 180 mg per week.
Embodiment 32. 29. The method of embodiment 29, wherein the dose ranges from about 30 mg to about 120 mg per week.
Embodiment 33. 29. The method of embodiment 29, wherein the dose ranges from about 60 mg to about 120 mg per week.
Embodiment 34. 29. The method of embodiment 29, wherein the dose is about 60 mg per week.
Embodiment 35. 29. The method of embodiment 29, wherein the dose is about 90 mg per week.
Embodiment 36. 29. The method of embodiment 29, wherein the dose is about 120 mg per week.
Embodiment 37. 29. The method of embodiment 29, wherein the dose is about 180 mg per week.
Embodiment 38. 29. The method of embodiment 29, wherein the dose is about 210 mg per week.
Embodiment 39. 29. The method of embodiment 29, wherein the dose is about 240 mg per week.
Embodiment 40. The compound or crystalline salt thereof is about 320 mg or less, about 240 mg or less, about 210 or less, about 180 or less, about 120 or less, about 90. The method according to any one of embodiments 1 to 28, wherein the method is administered at a weekly dose of about 60 or less, or about 30 or less.
Embodiment 41. 40. The method of embodiment 40, wherein the dose is about 60 mg or less per week.
Embodiment 42. 40. The method of embodiment 40, wherein the dose is about 90 mg or less per week.
Embodiment 43. 40. The method of embodiment 40, wherein the dose is about 120 mg or less per week.
Embodiment 44. 40. The method of embodiment 40, wherein the dose is about 180 mg or less per week.
Embodiment 45. 40. The method of embodiment 40, wherein the dose is about 210 mg or less per week.
Embodiment 46. 40. The method of embodiment 40, wherein the dose is about 240 mg or less per week.
Embodiment 47. The method of any one of embodiments 29-46, wherein the dose is administered once a week.
Embodiment 48. The dose is 2 or more partial doses, 3 or more partial doses, 4 or more partial doses, 5 or more partial doses over a week's course. The method of any one of embodiments 29-46, which is administered in a partial dose, 6 or more partial doses, or a daily partial dose.
Embodiment 49. The method of any one of embodiments 29-48, wherein the subject is a pediatric patient and the dose is between about 80% and 100% of the dose range.
Embodiment 50. 49. The method of embodiment 49, wherein the dose is adjusted to about 80%, 85%, 90%, or 95% of the dose range.
Embodiment 51. 49. The method of embodiment 49, wherein the dose ranges from about 8 mg to about 320 mg per week.
Embodiment 52. 49. The method of embodiment 49, wherein the dose ranges from about 24 mg to about 240 mg per week.
Embodiment 53. 49. The method of embodiment 49, wherein the dose ranges from about 24 mg to about 120 mg per week.
Embodiment 54. 49. The method of embodiment 49, wherein the dose ranges from about 48 mg to about 120 mg per week.
Embodiment 55. 49. The method of embodiment 49, wherein the dose ranges from about 72 mg to about 120 mg per week.
Embodiment 56. 49. The method of embodiment 49, wherein the dose ranges from about 96 mg to about 120 mg per week.
Embodiment 57. The method of any one of embodiments 1-56, wherein the subject has a predetermined hepcidin level of at least about 0.1 ng / mL.
Embodiment 58. 58. The method of embodiment 57, wherein the predetermined hepcidin level ranges from about 10 ng / mL to about 200 ng / mL.
Embodiment 59. The method of any one of embodiments 1-58, further comprising determining the hepcidin level of the subject after administration of the compound or crystalline salt thereof.
Embodiment 60. The method of any one of embodiments 1-59, further comprising determining the transferrin saturation level of the subject after administration of the compound or crystalline salt thereof.
Embodiment 61. The method of embodiment 60, wherein the transferrin saturation level is less than about 50%.
Embodiment 62. The method of embodiment 60, wherein the transferrin saturation level is less than about 45%.
Embodiment 63. The method of embodiment 60, wherein the transferrin saturation level is less than about 40%.
Embodiment 64. The method of any one of embodiments 1-63, wherein the compound or crystalline salt thereof is administered over one or more treatment cycles, each cycle comprising 4 weeks.
Embodiment 65. 13. The method of embodiment 64, wherein the method further comprises one or more rest days between treatment cycles.
Embodiment 66. The method according to embodiment 65, wherein the rest day is selected from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks.
Embodiment 67. A method for treating a disease or disorder that is susceptible to inhibition of ACVR1, said method is a therapeutically effective amount formula for a subject requiring treatment of a disease or disorder that is susceptible to inhibition of ACVR1. (2):

A method comprising administering a compound of, or a crystalline salt thereof, wherein the compound is administered at a dose ranging from about 10 mg to about 320 mg per week.
Embodiment 68. 67. The method of embodiment 67, wherein the dose ranges from about 30 mg to about 240 mg per week.
Embodiment 69. 67. The method of embodiment 67, wherein the dose ranges from about 60 mg to about 180 mg per week.
Embodiment 70. 67. The method of embodiment 67, wherein the dose ranges from about 30 mg to about 120 mg per week.
Embodiment 71. 67. The method of embodiment 67, wherein the dose ranges from about 60 mg to about 120 mg per week.
Embodiment 72. 67. The method of embodiment 67, wherein the dose is about 60 mg per week.
Embodiment 73. 67. The method of embodiment 67, wherein the dose is about 90 mg per week.
Embodiment 74. 67. The method of embodiment 67, wherein the dose is about 120 mg per week.
Embodiment 75. 67. The method of embodiment 67, wherein the dose is about 180 mg per week.
Embodiment 76. 67. The method of embodiment 67, wherein the dose is about 210 mg per week.
Embodiment 77. 67. The method of embodiment 67, wherein the dose is about 240 mg per week.
Embodiment 78. The compound or crystalline salt thereof is about 320 mg or less, about 240 mg or less, about 210 or less, about 180 or less, about 120 or less, about 90. 30. The method of any one of embodiments 67-77, which is administered at a weekly dose of about 60 or less, or about 30 or less.
Embodiment 79. 28. The method of embodiment 78, wherein the dose is about 60 mg or less per week.
80. 28. The method of embodiment 78, wherein the dose is about 90 mg or less per week.
Embodiment 81. 28. The method of embodiment 78, wherein the dose is about 120 mg or less per week.
Embodiment 82. 28. The method of embodiment 78, wherein the dose is about 180 mg or less per week.
Embodiment 83. 28. The method of embodiment 78, wherein the dose is about 210 mg or less per week.
Embodiment 84. 28. The method of embodiment 78, wherein the dose is about 240 mg or less per week.
Embodiment 85. The method of any one of embodiments 67-84, wherein the subject is a pediatric patient and the dose is between about 80% and 100% of the dose range.
Embodiment 86. 85. The method of embodiment 85, wherein the dose is about 80%, 85%, 90%, or 95% of the dose range.
Embodiment 87. The method of embodiment 85, wherein the dose ranges from about 8 mg to about 320 mg per week.
Embodiment 88. The method of embodiment 85, wherein the dose ranges from about 24 mg to about 240 mg per week.
Embodiment 89. The method of embodiment 85, wherein the dose ranges from about 24 mg to about 120 mg per week.
Embodiment 90. The method of embodiment 85, wherein the dose ranges from about 48 mg to about 120 mg per week.
Embodiment 91. The method of embodiment 85, wherein the dose ranges from about 72 mg to about 120 mg per week.
Embodiment 92. The method of embodiment 85, wherein the dose ranges from about 96 mg to about 120 mg per week.
Embodiment 93. The method of any one of embodiments 67-92, wherein the dose is administered once a week.
Embodiment 94. The method of any one of embodiments 67-92, wherein the dose is administered in two partial doses over a one-week course.
Embodiment 95. The method of any one of embodiments 67-92, wherein the dose is administered in three partial doses over a one-week course.
Embodiment 96. The method of any one of embodiments 67-92, wherein the dose is administered in four partial doses over a one-week course.
Embodiment 97. The method of any one of embodiments 67-92, wherein the dose is administered in 5 partial doses over a week of cool.
Embodiment 98. The method of any one of embodiments 67-92, wherein the dose is administered in 6 partial doses over a week of cool.
Embodiment 99. The method of any one of embodiments 67-92, wherein the dose is administered in daily partial doses.
Embodiment 100. The method of any one of embodiments 67-99, wherein the subject has a predetermined gene profile that comprises one or more mutations in the ACVR1 gene.
Embodiment 101. The method of embodiment 100, wherein the one or more mutations in the ACVR1 gene are activating mutations.
Embodiment 102. One or more mutations in the ACVR1 gene encode an ACVR1 polypeptide containing amino acid substitutions at one or more amino acid residues selected from R206H, G328V, R258G, or a combination thereof. The method according to embodiment 101.
Embodiment 103. 10. The method of embodiment 102, wherein the amino acid substitution in the ACVR1 polypeptide comprises R206H.
Embodiment 104. The method according to any one of embodiments 67 to 103, wherein the compound or a crystalline salt thereof is orally administered.
Embodiment 105. The disease or disorder is diffuse true pontine glioma, pontine tumor histologically diagnosed as grade II to IV invasive glioma, solid tumor, progressive ossifying fibrodysplasia, and chronic disease. The method of any one of embodiments 67-104, which is selected from one or more of anemia.
Embodiment 106. The method according to embodiment 105, wherein the compound or a crystalline salt thereof is administered as a solid dose preparation.
Embodiment 107. The method according to embodiment 105, wherein the compound or a crystalline salt thereof is administered as a liquid dose preparation.
Embodiment 108. The method of any one of embodiments 67-107, wherein the subject is monitored for hepcidin levels to determine any modification of the dose.
Embodiment 109. The method of any one of embodiments 67-108, wherein the subject is monitored for accumulation of the compound in one or more organs.
Embodiment 110. The method according to any one of embodiments 67 to 109, wherein the crystalline salt is an acid addition salt.
Embodiment 111. The method according to embodiment 110, wherein the acid addition salt is a hydrochloride salt.
Embodiment 112. 11. The method of embodiment 111, wherein the hydrochloride salt is monovalent.
Embodiment 113. The method according to any one of embodiments 110 to 112, wherein the crystalline salt form is anhydrous.
Embodiment 114. One or more pharmaceutically acceptable excipients and formula (2):

An oral solid pharmaceutical composition comprising the compound of the above or a crystalline salt thereof, wherein the compound is formulated with a titer of between about 5 mg and about 125 mg with respect to the weight of the free base.
Embodiment 115. The pharmaceutical composition according to embodiment 114, wherein the crystalline salt is an acid addition salt.
Embodiment 116. The pharmaceutical composition according to embodiment 115, wherein the acid addition salt is a hydrochloride salt.
Embodiment 117. The pharmaceutical composition according to embodiment 116, wherein the hydrochloride salt is monovalent.
Embodiment 118. The pharmaceutical composition according to any one of embodiments 115 to 117, wherein the crystalline salt form is anhydrous.
Embodiment 119. The pharmaceutical composition according to any one of embodiments 114 to 118, wherein the pharmaceutical composition is a gelatin capsule.
Embodiment 120. 119. The pharmaceutical composition according to embodiment 119, wherein the gelatin capsule has a titer of (i) 5 mg, (ii) 25 mg, or (iii) 125 mg relative to the weight of the free base.
Embodiment 121. 119. The pharmaceutical composition according to embodiment 119, wherein the gelatin capsule is (i) 30 mg, (ii) 60 mg, (iii) 90 mg, or (iv) 120 mg based on the weight of the free base.
Embodiment 122. Any of embodiments 114-121, wherein one or more pharmaceutical excipients are selected from microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate, or a combination thereof. The pharmaceutical composition according to one.
Embodiment 123. Equation (2):

With a compound of or a crystalline salt thereof;
(I) One or more buffers;
(Ii) One or more preservatives as needed;
(Iii) One or more solvents as needed;
An oral liquid pharmaceutical composition comprising (iv) one or more flavoring agents as needed; and (v) one or more additional pH regulators as needed.
Embodiment 124. The pharmaceutical composition according to embodiment 123, wherein the crystalline salt is an acid addition salt.
Embodiment 125. The pharmaceutical composition according to embodiment 124, wherein the acid addition salt is a hydrochloride salt.
Embodiment 126. The pharmaceutical composition according to embodiment 125, wherein the hydrochloride salt is monovalent.
Embodiment 127. The pharmaceutical composition according to any one of embodiments 124 to 126, wherein the crystalline salt form is anhydrous.
Embodiment 128. The pharmaceutical composition according to any one of embodiments 123 to 127, wherein the composition has a pH between about 2.0 and about 5.0.
Embodiment 129. The pharmaceutical composition according to embodiment 128, wherein the composition has a pH between about 2.0 and about 3.5.
Embodiment 130. The pharmaceutical composition according to embodiment 128, wherein the composition has a pH of about 2.0.
Embodiment 131. The pharmaceutical composition according to any one of embodiments 123 to 130, wherein the buffer is selected from citric acid, tartaric acid, malic acid, or acetic acid.
Embodiment 132. The pharmaceutical composition according to embodiment 131, wherein the buffer is malic acid.
Embodiment 133. The pharmaceutical composition according to embodiment 132, wherein the malic acid is DL-malic acid.
Embodiment 134. The pharmaceutical composition according to any one of embodiments 123 to 133, comprising one or more preservatives.
Embodiment 135. The pharmaceutical composition according to embodiment 134, wherein the preservative is selected from benzoic acid, sodium benzoate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or propylene glycol.
Embodiment 136. The pharmaceutical composition according to embodiment 135, wherein the preservative is benzoic acid.
Embodiment 137. The pharmaceutical composition according to embodiment 136, wherein the benzoic acid is a preservative and a buffer.
Embodiment 138. The pharmaceutical composition according to any one of embodiments 123 to 137, comprising one or more flavoring agents.
Embodiment 139. The pharmaceutical composition according to embodiment 138, wherein the flavoring agent is selected from sucralose, glycerin, cyclodextrin, HP-β-cyclodextrin, α-cyclodextrin, β-cyclodextrin, or a combination thereof.
Embodiment 140. The pharmaceutical composition according to embodiment 138, wherein the flavoring agent is a combination of HP-β-cyclodextrin and sucralose.
Embodiment 141. The pharmaceutical composition according to any one of embodiments 123 to 140, wherein the composition comprises the compound of formula (2) or a crystalline salt thereof at a concentration of about 10 mg / mL.
Embodiment 142. The pharmaceutical composition according to any one of embodiments 123 to 141, wherein the composition comprises malic acid at a concentration of up to about 6.7 mg / mL.
Embodiment 143. The pharmaceutical composition according to embodiment 142, wherein the composition comprises malic acid at a concentration of about 1.3 mg / mL.
Embodiment 144. The pharmaceutical composition according to any one of embodiments 123 to 143, wherein the composition comprises HP-β-cyclodextrin at a concentration of up to about 300 mg / mL.
Embodiment 145. The pharmaceutical composition according to embodiment 144, wherein the composition comprises HP-β-cyclodextrin at a concentration of up to about 150 mg / mL.
Embodiment 146. The pharmaceutical composition according to any one of embodiments 123 to 145, wherein the composition comprises sucralose at a concentration of up to about 2.0 mg / mL.
Embodiment 147. The pharmaceutical composition according to embodiment 146, wherein the composition comprises sucralose at a concentration of about 1.0 mg / mL.
Embodiment 148. The pharmaceutical composition according to any one of embodiments 123 to 147, wherein the composition comprises benzoic acid at a concentration of up to about 3.0 mg / mL.
Embodiment 149. The pharmaceutical composition according to embodiment 148, wherein the composition comprises benzoic acid at a concentration of up to about 2.0 mg / mL.
Embodiment 150. The pharmaceutical composition according to any one of embodiments 123 to 149, wherein the pH is adjusted to about 2.0 with hydrochloric acid.
Embodiment 151. The pharmaceutical composition according to any one of embodiments 123 to 150, wherein the solvent is water.
Embodiment 152. Compound (2)

N ⁴ - (2,2'-bipyridine-3-yl) ^-N 2 - crystalline form of (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) salts of pyrimidine-2,4-diamine ..
Embodiment 153. The crystalline form according to embodiment 152, wherein the salt is a pharmaceutically acceptable salt.
Embodiment 154. The crystalline form according to embodiment 153, wherein the pharmaceutically acceptable salt is an HCl salt.
Embodiment 155. The crystal form according to any one of embodiments 152 to 154, comprising embodiment A.
Embodiment 156. The crystal form according to any one of embodiments 152 to 154, which is essentially the same as the form A.
Embodiment 157. The crystalline form according to embodiment 155 or 156, wherein Form A is substantially free of impurities.
Embodiment 158. Of (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2,4-diamine anhydrous hydrochloride, - N ⁴ - (2,2'- bipyridine-3-yl) ^-N 2 Compound form A.
Embodiment 159. N, characterized by an x-ray diffraction pattern (XRPD) containing one or more 2θ values selected from 13.53, 16.14, 17.67, 18.38, 24.96, and 28.18. ⁴ - (2,2'-bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin-1-yl) phenyl) compound form of pyrimidine-2,4-diamine in anhydrous hydrochloride A.
Embodiment 160. Embodiment A according to embodiment 159, wherein the embodiment is characterized by two or more of the listed 2θ values.
Embodiment 161. Embodiment A according to embodiment 159, wherein the embodiment is characterized by three or more of the listed 2θ values.
Embodiment 162. Embodiment A according to embodiment 159, wherein the embodiment is characterized by four or more of the listed 2θ values.
Embodiment 163. Embodiment A according to embodiment 159, wherein the embodiment is characterized by five or more of the listed 2θ values.
Embodiment 164. The embodiment A according to the embodiment 159, wherein the embodiment is characterized by all six of the listed 2θ values.
Embodiment 165. A form according to any one of embodiments 157 to 164, further comprising one or more 2θ values selected from 6.71, 19.25, 23.98, and 29.60.
Embodiment 166. Embodiment A according to embodiment 165, wherein the embodiment is characterized by two or more of the listed 2θ values.
Embodiment 167. Embodiment A according to embodiment 165, wherein the embodiment is characterized by three or more of the listed 2θ values.
Embodiment 168. The embodiment A according to the embodiment 165, wherein the embodiment features all four of the listed 2θ values.
Embodiment 169. The X-ray powder diffractometer uses the X-ray wavelength of Cu kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.5444426, and has a Kα2 / Kα1 intensity ratio of 0.50, and X-rays. The embodiment A according to any one of embodiments 158 to 168, wherein the tube is set to 45 kV, 40 mA and used in the reflection mode.
Embodiment 170. The embodiment A according to any one of embodiments 158 to 169, wherein the 2θ value is within ± 0.2 2θ.
Embodiment 171. And wherein Figure 12 is substantially the same x-ray diffraction pattern ^{(XRPD), N 4 - (} 2,2'- bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin Compound form A of -1-yl) phenyl) pyrimidine-2,4-diamine anhydride.
Embodiment 172. 196.2 ° C., characterized by endotherm at one or more of 214.8 ° C., and 274.0 ^℃, N 4 - (2,2'- bipyridine-3-yl) ^-N 2 - ( Compound form A of 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2,4-diamine anhydride.
Embodiment 173. A.
Embodiment 174. A. Of the embodiment 172 or 173, further characterized by a starting temperature of 274.0 ° C.
Embodiment 175. The A according to any one of embodiments 172 to 174, further characterized by a weight loss of 1.7% up to 150 ° C.
Embodiment 176. Figure 15 is substantially characterized in the same TGA-DSC thermogram ^and, N 4 - (2,2'-bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin -1 -Il) Phenyl) Pyrimidine-2,4-Diamine Anhydrous Hydrochloride Compound Form A.
Embodiment 177. A pharmaceutical composition comprising the crystalline form according to any one of embodiments 152 to 176.
Embodiment 178. The pharmaceutical composition according to embodiment 176 as a solid-dose formulation.
Embodiment 179. The oral solid pharmaceutical composition according to any one of embodiments 114 to 122, wherein the compound is in the crystalline form according to any one of embodiments 152 to 176.
Embodiment 180. The pharmaceutical composition according to embodiment 176 as a liquid-dose formulation.
Embodiment 181. The oral liquid pharmaceutical composition according to any one of embodiments 123 to 151, wherein the compound is in the crystalline form according to any one of embodiments 152 to 176.
Embodiment 182. The method according to any one of embodiments 1 to 113, wherein the compound is in the crystalline form according to any one of embodiments 152 to 176.

（式中：
Ｒ^１は、Ｈ、またはＣ_１〜Ｃ_６アルコキシであり；
Ｒ^２は、Ｃ_１〜Ｃ_６アルコキシまたはヘテロシクリルであり；
Ｒ^３は、ハロ、またはＣ_１〜Ｃ_６アルコキシであり；
Ｒ^４は、Ｈ、またはＣ_１〜Ｃ_６アルキルである）
またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有する、方法。
実施形態２’． 前記疾患ががんである、実施形態１’に記載の方法。
実施形態３’． 前記がんが固形がんである、実施形態２’に記載の方法。
実施形態４’． 前記がんが、脳がん、子宮がん、卵巣がん、子宮頸がん、肺がん、乳がん、結腸がん、胃腸がん、造血もしくはリンパ系がん、皮膚がん、または骨がんである、実施形態２’または３’に記載の方法。
実施形態５’． 前記がんが脳がんである、実施形態２’〜４’のいずれか１つに記載の方法。
実施形態６’． 前記脳がんが、脳幹グリオーマである、実施形態５’に記載の方法。
実施形態７’． 前記脳がんが、びまん性真性橋膠腫（ＤＩＰＧ）である、実施形態５’または６’に記載の方法。
実施形態８’． 前記がんが、子宮、卵巣、または子宮頸がんである、実施形態２’〜４’のいずれか１つに記載の方法。
実施形態９’． 前記子宮がんが、子宮内膜がんである、実施形態８’に記載の方法。
実施形態１０’． 前記がんが、肺がんである、実施形態２’〜４’のいずれか１つに記載の方法。
実施形態１１’． 前記肺がんが、非小細胞性肺がんである、実施形態１０’に記載の方法。
実施形態１２’． 前記がんが、乳がんである、実施形態２’〜４’のいずれか１つに記載の方法。
実施形態１３’． 前記がんが、結腸がんである、実施形態２’〜４’のいずれか１つに記載の方法。
実施形態１４’． 前記がんが、黒色腫である、実施形態２’〜４’のいずれか１つに記載の方法。
実施形態１５’． 前記疾患が、進行性骨化性線維異形成症である、実施形態１’に記載の方法。
実施形態１６’． びまん性真性橋膠腫（ＤＩＰＧ）の処置を必要とする対象のびまん性真性橋膠腫（ＤＩＰＧ）を処置する方法であって、前記方法は、ＡＣＶＲ１阻害剤を含む処置レジメンを前記対象に投与することを含み、前記ＡＣＶＲ１阻害剤が、下記の構造（Ｉ）：

（式中：
Ｒ^１は、Ｈ、またはＣ_１〜Ｃ_６アルコキシであり；
Ｒ^２は、Ｃ_１〜Ｃ_６アルコキシまたはヘテロシクリルであり；
Ｒ^３は、ハロ、またはＣ_１〜Ｃ_６アルコキシであり；および
Ｒ^４は、Ｈ、またはＣ_１〜Ｃ_６アルキルである）
またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有する、方法。
実施形態１７’． 前記処置レジメンが、治療剤を投与することをさらに含む、実施形態１’〜１６’のいずれか１つに記載の方法。
実施形態１８’． 前記対象が、小児対象である、実施形態１’〜１７’のいずれか１つに記載の方法。
実施形態１９’． 進行性骨化性線維異形成症（ＦＯＰ）の処置を必要とする対象の進行性骨化性線維異形成症（ＦＯＰ）を処置する方法であって、前記方法は、処置レジメンを前記対象に投与することを含み、前記処置レジメンは、ＡＣＶＲ１阻害剤および治療剤を含み、前記ＡＣＶＲ１阻害剤が、下記の構造（Ｉ）：

（式中：
Ｒ^１は、Ｈ、またはＣ_１〜Ｃ_６アルコキシであり；
Ｒ^２は、Ｃ_１〜Ｃ_６アルコキシまたはヘテロシクリルであり；
Ｒ^３は、ハロ、またはＣ_１〜Ｃ_６アルコキシであり；および
Ｒ^４は、Ｈ、またはＣ_１〜Ｃ_６アルキルである）
またはその立体異性体、薬学的に許容される塩、互変異性体、もしくはプロドラッグを有する、方法。
実施形態２０’． 前記対象が、ＡＣＶＲ１遺伝子中に１つまたはそれより多くの変異を含む所定の遺伝子プロファイルを有する、実施形態１６’〜１９’のいずれか１つに記載の方法。
実施形態２１’． 前記ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、ミスセンス変異、フレームシフト変異、スプライス部位変異、またはこれらの組合せを含む、実施形態１’〜１５’または２０’のいずれか１つに記載の方法。
実施形態２２’． 前記１つまたはそれより多くの変異が、（Ｐ１９７Ｆ１９８）Ｌ、Ｃ５０９Ｓ、Ｄ１８５Ｇ、Ｄ１８５Ｎ、Ｄ４３３Ｎ、Ｅ３８ＦＳ、Ｆ２６５Ｓ、Ｇ２２５Ｄ、Ｇ２６４Ｓ、Ｇ３２８Ｅ、Ｇ３２８Ｒ、Ｇ３２８Ｖ、Ｇ３２８Ｗ、Ｇ３５６Ｄ、Ｇ５０Ｃ、Ｈ３２０Ｙ、Ｉ３２３Ｖ、Ｋ３１Ｅ、Ｋ３４５Ｑ、Ｌ１９６Ｐ、Ｌ２５１Ｓ、Ｍ３４Ｉ、Ｎ１００Ｄ、Ｎ４８１Ｉ、Ｐ１１５Ｓ、Ｐ４５５Ａ、Ｑ２０７Ｅ、Ｑ２７８Ｐ、Ｒ２０１Ｉ、Ｒ２０６Ｃ、Ｒ２０６Ｈ、Ｒ２５８Ｇ、Ｒ２５８Ｓ、Ｒ３０７Ｑ、Ｒ３２５Ａ、Ｒ３７５Ｃ、Ｒ３７５Ｐ、Ｒ４０１Ｍ、Ｒ４９０Ｈ、Ｓ１３０Ｆ、Ｓ２２６Ｎ、Ｓ４１Ｆ、Ｓ４４０Ｇ、Ｓ４６９Ｃ、Ｓ５６Ｌ、Ｔ２９８Ｓ、Ｖ２３４Ｍ、Ｖ９１Ｍ、Ｗ９８Ｒ、またはこれらの組合せを含む、実施形態１’〜１５’、２０’、または２１’のいずれか１つに記載の方法。
実施形態２３’． 前記ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、ミスセンス変異を含む、実施形態１’〜１５’または２０’のいずれか１つの方法。
実施形態２４’ 前記ミスセンス変異が、Ｃ５０９Ｓ、Ｄ１８５Ｎ、Ｄ４３３Ｎ、Ｆ２６５Ｓ、Ｇ２２５Ｄ、Ｈ３２０Ｙ、Ｉ３２３Ｖ、Ｋ３１Ｅ、Ｋ３４５Ｑ、Ｍ３４Ｉ、Ｎ１００Ｄ、Ｎ４８１Ｉ、Ｐ１１５Ｓ、Ｐ４５５Ａ、Ｑ２７８Ｐ、Ｒ２０６Ｃ、Ｒ４０１Ｍ、Ｓ１３０Ｆ、Ｓ２２６Ｎ、Ｓ４１Ｆ、Ｓ４１Ｆ、Ｓ４４０Ｇ、Ｓ４６９Ｃ、Ｓ５６Ｌ、Ｔ２９８Ｓ、Ｖ２３４Ｍ、Ｖ９１Ｍ、またはＷ９８Ｒである、実施形態２１’または２３’に記載の方法。
実施形態２５’． 前記ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、フレームシフト変異を含む、実施形態１’〜１６’または２０’のいずれか１つに記載の方法。
実施形態２６’． 前記フレームシフト変異がＥ３８ｆｓである、実施形態２１’または２５’に記載の方法。
実施形態２７’． 前記ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、スプライス部位変異を含む、実施形態１’〜１５’または２０’のいずれか１つに記載の方法。
実施形態２８’． 前記スプライス部位変異が、Ｇ２６４Ｓである、実施形態２１’または２７’に記載の方法。
実施形態２９’． 前記ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、Ｒ２０６Ｈ、Ｇ３２８Ｖ、Ｒ２５８Ｇ、またはこれらの組合せを含む、実施形態１’〜１５’または２０’〜２２’のいずれか１つに記載の方法。
実施形態３０’． 前記ＡＣＶＲ１遺伝子中の前記１つまたはそれより多くの変異が、Ｒ２０６Ｈを含む、実施形態１’〜１５’、２０’〜２２’、または２９’のいずれか１つに記載の方法。
実施形態３１’． 前記対象が、少なくとも約０．１ｎｇ／ｍＬの所定のヘプシジンレベルを有する、実施形態１’〜３０’のいずれか１つに記載の方法。
実施形態３２’． 前記所定のヘプシジンレベルが、約１０ｎｇ／ｍＬから約３５ｎｇ／ｍＬに及ぶ、実施形態３１’の方法。
実施形態３３’． 前記ＡＣＶＲ１阻害剤が投与された後にヘプシジンレベルを決定することをさらに含む、実施形態１’〜３２’のいずれか１つに記載の方法。
実施形態３４’． 前記対象が、約５０％未満の所定のトランスフェリン飽和レベルを有する、実施形態１’〜３３’のいずれか１つに記載の方法。
実施形態３５’． 前記対象が、約４５％未満の所定のトランスフェリン飽和レベルを有する、実施形態１’〜３３’のいずれか１つに記載の方法。
実施形態３６’． 前記対象が、約４０％未満の所定のトランスフェリン飽和レベルを有する、実施形態１’〜３３’のいずれか１つに記載の方法。
実施形態３７’． 前記ＡＣＶＲ１阻害剤が、１日当たり約１０ｍｇから約３２０ｍｇに及ぶ用量で投与される、実施形態１’〜３６’のいずれか１つに記載の方法。
実施形態３８’． 前記用量が、１日当たり約３０ｍｇから約２４０ｍｇに及ぶ、実施形態３７’に記載の方法。
実施形態３９’． 前記用量が、１日当たり約６０ｍｇから約１８０ｍｇに及ぶ、実施形態３７’または３８’に記載の方法。
実施形態４０’． 前記用量が、１日当たり約２５ｍｇ；１日当たり約３０ｍｇ；１日当たり約６０ｍｇ；１日当たり約１２０ｍｇ；１日当たり約１２５ｍｇ；１日当たり約１８０ｍｇ；１日当たり約２４０ｍｇ；１日当たり約２５０ｍｇ；１日当たり約３２０ｍｇ；または１日当たり約３２５ｍｇである、実施形態３７’〜３９’のいずれか１つに記載の方法。
実施形態４１’． Ｒ^１がＨである、実施形態１’〜４０’のいずれか１つに記載の方法。
実施形態４２’． Ｒ^１がＣ_１〜Ｃ_６アルコキシである、実施形態１’〜４０’のいずれか１つに記載の方法。
実施形態４３’． 前記Ｃ_１〜Ｃ_６アルコキシがメトキシである、実施形態４２’に記載の方法。
実施形態４４’． Ｒ^２がＣ_１〜Ｃ_６アルコキシである、実施形態１’〜４３’のいずれか１つに記載の方法。
実施形態４５’． 前記Ｃ_１〜Ｃ_６アルコキシがメトキシである、実施形態４４’に記載の方法。
実施形態４６’． Ｒ^２がヘテロシクリルである、実施形態１’〜４５’のいずれか１つに記載の方法。
実施形態４７’． 前記ヘテロシクリルが、必要に応じて置換されたピペラジニルである、実施形態４６’に記載の方法。
実施形態４８’． 前記必要に応じて置換されたピペラジニルが、Ｃ_１〜Ｃ_６アルキルまたはＣ_１〜Ｃ_６ヒドロキシアルキルで置換される、実施形態４７’に記載の方法。
実施形態４９’． Ｒ^３がハロである、実施形態１’〜４８’のいずれか１つに記載の方法。
実施形態５０’． 前記ハロがクロロである、実施形態４９’に記載の方法。
実施形態５１’． Ｒ^３がＣ_１〜Ｃ_６アルコキシである、実施形態１’〜４８’のいずれか１つに記載の方法。
実施形態５２’． 前記Ｃ_１〜Ｃ_６アルコキシがメトキシである、実施形態５１’に記載の方法。
実施形態５３’． Ｒ^４がＨである、実施形態１’〜５２’のいずれか１つに記載の方法。
実施形態５４’． Ｒ^４がＣ_１〜Ｃ_６アルキルである、実施形態１’〜５２’のいずれか１つに記載の方法。
実施形態５５’． 前記Ｃ_１〜Ｃ_６アルキルがメチルである、実施形態５４’に記載の方法。
実施形態５６’． 下記の構造：

を有する、実施形態１’〜４０’のいずれか１つに記載の方法。
実施形態５７’． 下記の構造：

を有する、実施形態１’〜４０’のいずれか１つに記載の方法。
実施形態５８’． 下記の構造：

を有する、実施形態１’〜４０’のいずれか１つに記載の方法。
実施形態５９’． 下記の構造：

を有する、実施形態１’〜４０’のいずれか１つに記載の化合物。
実施形態６０’． 下記の構造：

を有する、実施形態１’〜４０’のいずれか１つに記載の方法。
実施形態６１’． 下記の構造：

を有する、実施形態１’〜４０’のいずれか１つに記載の方法。
実施形態６２’． 前記治療剤が：
レチノイン酸受容体ガンマアゴニスト；ｍＴＯＲ阻害剤；アクチビンＡ抗体；キナーゼ阻害剤；ＡＣＶＲ１抗体；ＴＡＫ１阻害剤；ホスホジエステラーゼ阻害剤；ＨＤＡＣ阻害剤；化学療法剤；免疫療法剤；細胞療法；ペプチドまたは腫瘍ライセートワクチン；イリノテカン；ＧＭ−ＣＳＦを含むＴＴＲＮＡ−ＤＣワクチン、ＴＴＲＮＡ−ｘＡＬＴ；インテグリン阻害剤；ＩＬ−１２療法；抗ネオプラストン療法；イミキモド；腫瘍溶解性アデノウイルス；ＷＥＥ１阻害剤；ＷＴ１タンパク質由来ペプチドワクチン；ペグ化インターフェロンアルファ２ｂ；キナーゼ抗体；円滑化阻害剤；チューブリン阻害剤；テロメラーゼ阻害剤；ＣＤ４０アゴニスト；ＧＭ−ＣＳＦアゴニスト；ＩＤＯ阻害剤；および
放射性ヨウ素標識モノクローナル抗体８Ｈ９．６４
から選択される、実施形態１７’〜６１’のいずれか１つに記載の方法。
実施形態６３’． 前記治療剤が：
レチノイン酸受容体ガンマアゴニスト；ｍＴＯＲ阻害剤；アクチビンＡ抗体；キナーゼ阻害剤；ＡＣＶＲ１抗体；ＴＡＫ１阻害剤；およびホスホジエステラーゼ阻害剤
から選択される、実施形態１７’〜６２’のいずれか１つに記載の方法。
実施形態６４’． 前記治療剤が：
ＨＤＡＣ阻害剤；化学療法剤；免疫療法剤；細胞療法；ペプチドまたは腫瘍ライセートワクチン；イリノテカン；ＧＭ−ＣＳＦを含むＴＴＲＮＡ−ＤＣワクチン、ＴＴＲＮＡ−ｘＡＬＴ；インテグリン阻害剤；ＩＬ−１２療法；抗ネオプラストン療法；イミキモド；腫瘍溶解性アデノウイルス；ＷＥＥ１阻害剤；ＷＴ１タンパク質由来ペプチドワクチン；
ペグ化インターフェロンアルファ２ｂ；キナーゼ抗体；キナーゼ阻害剤；円滑化阻害剤；チューブリン阻害剤；テロメラーゼ阻害剤；ＣＤ４０アゴニスト；ＧＭ−ＣＳＦアゴニスト；
ＩＤＯ阻害剤；および放射性ヨウ素標識モノクローナル抗体８Ｈ９
から選択される、実施形態１７’〜６２’のいずれか１つに記載の方法。
実施形態６５’． 前記キナーゼ阻害剤が、サイクリン依存性キナーゼ（ＣＤＫ）を阻害する、実施形態１７’〜６４’のいずれか１つに記載の方法。
実施形態６６’． 前記ＣＤＫが、ＣＤＫ９またはＣＤＫ７である、実施形態６５’に記載の方法。
実施形態６７’． 前記ＣＤＫがＣＤＫ９である、実施形態６５’に記載の方法。
実施形態６８’． 前記ＣＤＫ９阻害剤が、ｓｉＲＮＡ、アルボシジブ、またはそのプロドラッグ、ジナシクリブ、またはこれらの組合せである、実施形態６６’または６７’に記載の方法。
実施形態６９’． 前記キナーゼ阻害剤が、ホスホイノシチド３−キナーゼ（ＰＩ３Ｋ）を阻害する、実施形態１７’〜６４’のいずれか１つに記載の方法。
実施形態７０’． 前記免疫療法剤が、免疫チェックポイント阻害剤である、実施形態１７’〜６２’または６４’のいずれか１つに記載の方法。
実施形態７１’． 前記免疫チェックポイント阻害剤が、ＰＤ−１阻害剤である、実施形態７０’に記載の方法。
実施形態７２’． 前記ＰＤ−１阻害剤が、ペムブロリズマブ、ニボルマブ、またはこれらの組合せである、実施形態７１’に記載の方法。
実施形態７３’． 前記免疫チェックポイント阻害剤が、ＰＤ−Ｌ１阻害剤である、実施形態７０’に記載の方法。
実施形態７４’． 前記ＰＤ−Ｌ１阻害剤が、アテゾリズマブ、アベルマブ、デュラバルマブ、またはこれらの組合せである、実施形態７３’に記載の方法。
実施形態７５’． 前記キナーゼ抗体が薬物コンジュゲートを含む、実施形態１７’〜６４’のいずれか１つに記載の方法。
実施形態７６’． 前記レチノイン酸受容体ガンマアゴニストがパロバロテンであり；前記ｍＴＯＲ阻害剤がラパマイシンまたはエベロリムスであり；前記アクチビンＡ抗体がＲＥＧＮ２４４７であり；前記キナーゼ阻害剤が、サラカチニブ、モメロチニブ、ドルソモルフィン、イマチニブ、クリゾチニブ、ダサチニブ、ベバシズマブ、エルロチニブ、バンデタニブ、リボシクリブ、クレノラニブ、アベマシクリブ、ＯＮＣ２０１、シレンギジド、アルボシジブ、またはこれらのプロドラッグであり；前記ホスホジエステラーゼ阻害剤がジピリダモールであり；前記ＨＤＡＣ阻害剤が、ＳＡＨＡ、ボリノスタット、またはパノビノスタットであり；前記化学療法剤が、メルファラン、ゲムシタビン、テモゾロミド、シクロホスファミド、フルダラビン、ドキソルビシン、イリノテカン、レナリドミド、バルプロ酸、クロロキン、カルボプラチン、エトポシド、イフォスファミド、ポマリドミド、またはロムスチンであり；
前記免疫療法剤がＭＤＶ９３００であり；前記細胞療法が自家樹状細胞を含み；前記ペプチドまたは腫瘍ライセートワクチンが、Ｋ２７Ｍペプチドまたはリンドペピムトを含み；前記イリノテカンが、対流強化送達により投与され；前記インテグリン阻害剤がシレンギチドであり；前記抗ネオプラストン療法が、アテンゲナルまたはアスツゲナルであり；前記腫瘍溶解性アデノウイルスがＤＮＸ−２４０１であり；前記ＷＥＥ１阻害剤がＡＺＤ１７７５であり；前記ＷＴ１タンパク質由来ペプチドワクチンがＤＳＰ−７８８８であり；前記キナーゼ抗体が、ニモツズマブ、エルビタックス、またはＡＢＴ−４１４であり；前記円滑化阻害剤がビスモデギブであり；前記チューブリン阻害剤がメベンダゾールであり；
前記テロメラーゼ阻害剤がイメテルスタットであり；前記ＣＤ４０アゴニストがＡＰＸ００５Ｍであり；前記ＧＭ−ＣＳＦアゴニストがレオウイルスを含むサルグラモスチムであり；または前記ＩＤＯ阻害剤がインドキシモドである、
実施形態１７’〜６５’のいずれか１つに記載の方法。
実施形態７７’． 前記処置レジメンが、外科的切除、放射線療法、またはこれらの組合せをさらに含む、実施形態１’〜７６’のいずれか１つに記載の方法。
実施形態７８’． 前記薬学的に許容される塩が、酸付加塩である、実施形態１’〜７７’のいずれか１つに記載の方法。
実施形態７９’． 前記酸付加塩が、塩酸塩である、実施形態７８’に記載の方法。 Further embodiments and embodiments of the present disclosure that may be incorporated in various combinations include:
Embodiment 1'. A method of treating a disease in a subject requiring treatment of the disease, wherein the treatment regimen comprising an ACVR1 inhibitor comprises a predetermined mutation containing one or more mutations in the ACVR1 gene. The ACVR1 inhibitor comprises administration to said subject having a genetic profile and has the following structure (I):

(During the ceremony:
R ¹ is H, or C _{1 to} C ₆ alkoxy;
R ² _is C 1 -C ₆ alkoxy or heterocyclyl;
R ³ is halo or _C 1 -C ₆ alkoxy;
R ⁴ is H or _C 1 -C ₆ alkyl,)
Or a method having a stereoisomer thereof, a pharmaceutically acceptable salt, a tautomer, or a prodrug.
Embodiment 2'. The method according to embodiment 1', wherein the disease is cancer.
Embodiment 3'. The method according to embodiment 2', wherein the cancer is a solid cancer.
Embodiment 4'. The cancer is brain cancer, uterine cancer, ovarian cancer, cervical cancer, lung cancer, breast cancer, colon cancer, gastrointestinal cancer, hematopoietic or lymphoid cancer, skin cancer, or bone cancer. , The method according to embodiment 2'or 3'.
Embodiment 5'. The method according to any one of embodiments 2'to 4', wherein the cancer is brain cancer.
Embodiment 6'. The method according to embodiment 5', wherein the brain cancer is a brain stem glioma.
Embodiment 7'. The method according to embodiment 5'or 6', wherein the brain cancer is diffuse true pontine glioma (DIPG).
Embodiment 8'. The method according to any one of embodiments 2'-4', wherein the cancer is uterine, ovarian, or cervical cancer.
Embodiment 9'. The method according to embodiment 8', wherein the uterine cancer is endometrial cancer.
Embodiment 10'. The method according to any one of embodiments 2'-4', wherein the cancer is lung cancer.
Embodiment 11'. 10. The method of embodiment 10', wherein the lung cancer is non-small cell lung cancer.
Embodiment 12'. The method according to any one of embodiments 2'-4', wherein the cancer is breast cancer.
Embodiment 13'. The method according to any one of embodiments 2'-4', wherein the cancer is colon cancer.
Embodiment 14'. The method according to any one of embodiments 2'-4', wherein the cancer is melanoma.
Embodiment 15'. The method according to embodiment 1', wherein the disease is progressive ossifying fibrodysplasia.
Embodiment 16'. A method of treating diffuse true pontine glioma (DIPG) in a subject requiring treatment for diffuse true pontine glioma (DIPG), wherein the treatment regimen containing an ACVR1 inhibitor is administered to the subject. The ACVR1 inhibitor comprises the following structure (I):

(During the ceremony:
R ¹ is H, or C _{1 to} C ₆ alkoxy;
R ² _is C 1 -C ₆ alkoxy or heterocyclyl;
R ³ is halo, or C _{1 to} C ₆ alkoxy; and R ⁴ is H, or C _{1 to} C ₆ alkyl).
Or a method having a stereoisomer thereof, a pharmaceutically acceptable salt, a tautomer, or a prodrug.
Embodiment 17'. The method of any one of embodiments 1'-16', wherein the treatment regimen further comprises administering a therapeutic agent.
Embodiment 18'. The method according to any one of embodiments 1'to 17', wherein the subject is a pediatric subject.
Embodiment 19'. A method of treating progressive ossifying fibrodysplasia (FOP) in a subject requiring treatment for progressive ossifying fibrodysplasia (FOP), wherein the treatment regimen is applied to the subject. Including administration, the treatment regimen comprises an ACVR1 inhibitor and a therapeutic agent, wherein the ACVR1 inhibitor has the following structure (I):

(During the ceremony:
R ¹ is H, or C _{1 to} C ₆ alkoxy;
R ² _is C 1 -C ₆ alkoxy or heterocyclyl;
R ³ is halo, or C _{1 to} C ₆ alkoxy; and R ⁴ is H, or C _{1 to} C ₆ alkyl).
Or a method having a stereoisomer thereof, a pharmaceutically acceptable salt, a tautomer, or a prodrug.
20'. The method of any one of embodiments 16'-19', wherein the subject has a predetermined gene profile that comprises one or more mutations in the ACVR1 gene.
21'. One or more of the mutations in the ACVR1 gene is in any one of embodiments 1'-15' or 20', comprising a missense mutation, a frameshift mutation, a splice site mutation, or a combination thereof. The method described.
Embodiment 22'. One or more of the above mutations are (P197F198) L, C509S, D185G, D185N, D433N, E38FS, F265S, G225D, G264S, G328E, G328R, G328V, G328W, G356D, G50C, H320Y, I323V. K345Q, L196P, L251S, M34I, N100D, N481I, P115S, P455A, Q207E, Q278P, R201I, R206C, R206H, R258G, R258S, R307Q, R325A, R375C, R375P, R401M, R470S The method according to any one of embodiments 1'-15', 20', or 21', comprising S469C, S56L, T298S, V234M, V91M, W98R, or a combination thereof.
23'. The method of any one of embodiments 1'-15' or 20', wherein the one or more mutations in the ACVR1 gene include a missense mutation.
Embodiment 24'The missense mutations are C509S, D185N, D433N, F265S, G225D, H320Y, I323V, K31E, K345Q, M34I, N100D, N481I, P115S, P455A, Q278P, R206C, R401M, S130F, S226. , S440G, S469C, S56L, T298S, V234M, V91M, or W98R, according to embodiment 21'or 23'.
Embodiment 25'. The method of any one of embodiments 1'-16' or 20', wherein the one or more mutations in the ACVR1 gene include a frameshift mutation.
Embodiment 26'. 21'or 25'. The method of embodiment 21'or 25', wherein the frameshift mutation is E38fs.
Embodiment 27'. The method according to any one of embodiments 1'-15' or 20', wherein the one or more mutations in the ACVR1 gene include a splice site mutation.
Embodiment 28'. 21'or 27', wherein the splice site mutation is G264S.
Embodiment 29'. The one or more mutations in the ACVR1 gene according to any one of embodiments 1'-15' or 20'-22', comprising R206H, G328V, R258G, or a combination thereof. Method.
Embodiment 30'. The method according to any one of embodiments 1'-15', 20'-22', or 29', wherein the one or more mutations in the ACVR1 gene comprise R206H.
Embodiment 31'. The method of any one of embodiments 1'-30', wherein the subject has a predetermined hepcidin level of at least about 0.1 ng / mL.
Embodiment 32'. The method of embodiment 31', wherein the predetermined hepcidin level ranges from about 10 ng / mL to about 35 ng / mL.
Embodiment 33'. The method according to any one of embodiments 1'-32', further comprising determining hepcidin levels after administration of the ACVR1 inhibitor.
Embodiment 34'. The method of any one of embodiments 1'-33', wherein the subject has a predetermined transferrin saturation level of less than about 50%.
Embodiment 35'. The method of any one of embodiments 1'-33', wherein the subject has a predetermined transferrin saturation level of less than about 45%.
Embodiment 36'. The method of any one of embodiments 1'-33', wherein the subject has a predetermined transferrin saturation level of less than about 40%.
Embodiment 37'. The method of any one of embodiments 1'-36', wherein the ACVR1 inhibitor is administered at a dose ranging from about 10 mg to about 320 mg per day.
Embodiment 38'. 37'. The method of embodiment 37', wherein the dose ranges from about 30 mg to about 240 mg per day.
Embodiment 39'. 38'. The method of embodiment 37'or 38', wherein the dose ranges from about 60 mg to about 180 mg per day.
Embodiment 40'. The dose is about 25 mg per day; about 30 mg per day; about 60 mg per day; about 120 mg per day; about 125 mg per day; about 180 mg per day; about 240 mg per day; about 250 mg per day; about 320 mg per day; or The method according to any one of embodiments 37'-39', which is about 325 mg per day.
Embodiment 41'. The method according to any one of embodiments 1'-40', wherein R ^{1 is H.}
Embodiment 42'. The method according to any one of embodiments 1'-40', wherein R ¹ is C _{1 to} C _{6 alkoxy.}
Embodiment 43'. The method according to embodiment 42', wherein the C _{1 to} C _{6 alkoxy is methoxy.}
Embodiment 44'. The method according to any one of embodiments 1'to 43', wherein R ² is C _{1 to} C _{6 alkoxy.}
Embodiment 45'. The method according to embodiment 44', wherein the C _{1 to} C _{6 alkoxy is methoxy.}
Embodiment 46'. The method according to any one of embodiments 1'to 45', wherein R ^{2 is heterocyclyl.}
Embodiment 47'. 46'. The method of embodiment 46', wherein the heterocyclyl is a optionally substituted piperazinyl.
Embodiment 48'. Said piperazinyl is optionally _substituted, it is substituted by C 1 -C ₆ alkyl or _C 1 -C ₆ hydroxyalkyl, method of embodiment 47 '.
Embodiment 49'. The method according to any one of embodiments 1'to 48', wherein R ^{3 is halo.}
Embodiment 50'. The method according to embodiment 49', wherein the halo is chloro.
Embodiment 51'. The method according to any one of embodiments 1'to 48', wherein R ³ is C _{1 to} C _{6 alkoxy.}
Embodiment 52'. The method according to embodiment 51', wherein the C _{1 to} C _{6 alkoxy is methoxy.}
Embodiment 53'. The method according to any one of embodiments 1'to 52', wherein R ^{4 is H.}
Embodiment 54'. The method according to any one of embodiments 1'to 52', wherein R ⁴ is C _{1 to} C _{6 alkyl.}
Embodiment 55'. The method according to embodiment 54', wherein the C _{1 to} C _{6 alkyls are methyl.}
Embodiment 56'. Structure below:

The method according to any one of embodiments 1'to 40', which comprises.
Embodiment 57'. Structure below:

The method according to any one of embodiments 1'to 40', which comprises.
Embodiment 58'. Structure below:

The method according to any one of embodiments 1'to 40', which comprises.
Embodiment 59'. Structure below:

The compound according to any one of embodiments 1'to 40'.
Embodiment 60'. Structure below:

The method according to any one of embodiments 1'to 40', which comprises.
Embodiment 61'. Structure below:

The method according to any one of embodiments 1'to 40', which comprises.
Embodiment 62'. The therapeutic agent is:
Retinoic acid receptor gamma agonist; mTOR inhibitor; activin A antibody; kinase inhibitor; ACVR1 antibody; TAK1 inhibitor; phosphodiesterase inhibitor; HDAC inhibitor; chemotherapeutic agent; immunotherapeutic agent; cell therapy; peptide or tumor lysate vaccine Irinotecan; TTRNA-DC vaccine containing GM-CSF, TTRNA-xALT; integrin inhibitor; IL-12 therapy; anti-neoplastone therapy; imikimod; tumor-soluble adenovirus; WEE1 inhibitor; WT1 protein-derived peptide vaccine; peg Interferon alpha 2b; kinase antibody; smoothing inhibitor; tuberin inhibitor; telomerase inhibitor; CD40 agonist; GM-CSF agonist; IDO inhibitor; and radioactive iodine-labeled monoclonal antibody 8H9.64
The method according to any one of embodiments 17'to 61', which is selected from.
Embodiment 63'. The therapeutic agent is:
The retinoic acid receptor gamma agonist; mTOR inhibitor; activin A antibody; kinase inhibitor; ACVR1 antibody; TAK1 inhibitor; and phosphodiesterase inhibitor, according to any one of embodiments 17'-62'. Method.
Embodiment 64'. The therapeutic agent is:
HDAC inhibitor; chemotherapeutic agent; immunotherapeutic agent; cell therapy; peptide or tumor lysate vaccine; irinotecan; TTRNA-DC vaccine containing GM-CSF, TTRNA-xALT; integrin inhibitor; IL-12 therapy; anti-neoplaston therapy Imikimod; Tumor-dissolving adenovirus; WEE1 inhibitor; WT1 protein-derived peptide vaccine;
Pegylated interferon alpha 2b; kinase antibody; kinase inhibitor; smoothing inhibitor; tubulin inhibitor; telomerase inhibitor; CD40 agonist; GM-CSF agonist;
IDO inhibitor; and radioiodine-labeled monoclonal antibody 8H9
The method according to any one of embodiments 17'to 62', which is selected from.
Embodiment 65'. The method according to any one of embodiments 17'-64', wherein the kinase inhibitor inhibits a cyclin-dependent kinase (CDK).
Embodiment 66'. 65'. The method of embodiment 65', wherein the CDK is CDK9 or CDK7.
Embodiment 67'. 65'. The method of embodiment 65', wherein the CDK is CDK9.
Embodiment 68'. The method of embodiment 66'or 67', wherein the CDK9 inhibitor is siRNA, alvocidib, or a prodrug, dynasicrib, or a combination thereof.
Embodiment 69'. The method according to any one of embodiments 17'-64', wherein the kinase inhibitor inhibits phosphoinositide 3-kinase (PI3K).
Embodiment 70'. The method according to any one of embodiments 17'-62'or 64', wherein the immunotherapeutic agent is an immune checkpoint inhibitor.
Embodiment 71'. The method according to embodiment 70', wherein the immune checkpoint inhibitor is a PD-1 inhibitor.
Embodiment 72'. The method of embodiment 71', wherein the PD-1 inhibitor is pembrolizumab, nivolumab, or a combination thereof.
Embodiment 73'. The method according to embodiment 70', wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.
Embodiment 74'. The method according to embodiment 73', wherein the PD-L1 inhibitor is atezolizumab, avelumab, duravalumab, or a combination thereof.
Embodiment 75'. The method according to any one of embodiments 17'-64', wherein the kinase antibody comprises a drug conjugate.
Embodiment 76'. The retinoic acid receptor gamma agonist is parovarotene; the mTOR inhibitor is rapamycin or everolimus; the activin A antibody is REGN2447; the kinase inhibitors are salacatinib, momerotinib, dolsomorphin, imatinib, crizotinib, dasatinib. , Bebasizumab, erlotinib, bandetanib, ribocyclib, clenoranib, abemacicrib, ONC201, silengidide, arbosideib, or prodrugs thereof; said phosphodiesterase inhibitor is dipyridamole; said HDAC inhibitor is SAHA, bolinostat, or panobinot The chemotherapeutic agent is melphalan, gemcitabine, temozolomid, cyclophosphamide, fludarabine, doxorubicin, irinotecan, renalidemid, valproic acid, chloroquin, carboplatin, etoposide, ifosfamide, pomalidemid, or lomustine;
The immunotherapeutic agent is MDV9300; the cell therapy comprises autologous dendritic cells; the peptide or tumor lysate vaccine comprises K27M peptide or Lindpepimut; the irinotecan is administered by convection-enhanced delivery; the integrin inhibitor. Is sirengitide; the anti-neoplaston therapy is athenal or astugenal; the tumor-soluble adenovirus is DNX-2401; the WEE1 inhibitor is AZD1775; the WT1 protein-derived peptide vaccine is DSP-7888. The kinase antibody is nimotzumab, erbitux, or ABT-414; the smoothing inhibitor is bismodegib; the tubulin inhibitor is mebendazole;
The telomerase inhibitor is imeterstat; the CD40 agonist is APX005M; the GM-CSF agonist is sargramostim containing a reoviridae; or the IDO inhibitor is indoximod.
The method according to any one of embodiments 17'to 65'.
Embodiment 77'. The method of any one of embodiments 1'-76', wherein the treatment regimen further comprises surgical resection, radiation therapy, or a combination thereof.
Embodiment 78'. The method according to any one of embodiments 1'to 77', wherein the pharmaceutically acceptable salt is an acid addition salt.
Embodiment 79'. The method according to embodiment 78', wherein the acid addition salt is a hydrochloride salt.

The various embodiments described above may be combined to provide additional embodiments. All US patents, US patent application publications, US patent applications, non-US patents, non-US patent applications, and non-patent publications referred to herein and / or listed in the application datasheet are in their entirety. Is incorporated herein by reference. The embodiments may be modified, if necessary, to use the concepts of various patents, applications, and publications to provide yet other embodiments.

The experimental test compounds described herein were used in free or salt form, as noted.

The particular response observed may vary depending on and depending on the presence or absence of the particular active compound or carrier selected, as well as the type of formulation and the dosage form used, such. Variations or differences in expected outcomes are contemplated by the practice of the present invention.

These and other modifications can be made in the embodiment in the light of the above detailed description. In general, the terms used in the claims below should be construed as not limiting the scope of the claims to the particular embodiments disclosed herein and in the claims. It should be construed to include all possible embodiments, as well as the full range of equivalents provided by such claims. Therefore, the scope of claims is not limited by this disclosure.

Claims (182)

A method of treating diffuse true pontine glioma (DIPG) in a subject requiring treatment of diffuse true pontine glioma (DIPG), wherein the method is a therapeutically effective amount of equation (2) :.

A method comprising administering a compound of, or a crystalline salt thereof. The method according to claim 1, wherein the crystalline salt is an acid addition salt. The method according to claim 2, wherein the acid addition salt is a hydrochloride. The method according to claim 3, wherein the hydrochloride salt is monovalent. The method according to any one of claims 1 to 4, wherein the crystalline salt form is anhydrous. The method according to any one of claims 1 to 5, wherein the subject is a pediatric patient. The method according to any one of claims 1 to 5, wherein the subject is about 1 week to about 22 years old. The method according to any one of claims 1 to 7, wherein the subject is about 18 years old or younger. The method according to any one of claims 1 to 8, wherein the subject is about 10 years old or younger. The method according to any one of claims 1 to 9, wherein the subject is about 8 years old or younger. The method according to any one of claims 1 to 10, wherein the subject is about 6 years old or younger. The method according to any one of claims 1 to 11, wherein the DIPG is a newly diagnosed or recurrent. The method of any one of claims 1-12, wherein the DIPG is characterized as a pontine tumor histologically diagnosed as invasive glioma grade II to IV. The method according to any one of claims 1 to 13, further comprising administering radiation therapy. 14. The method of claim 14, wherein the administration of radiation is performed prior to administration of the compound or a crystalline salt thereof. 15. The method of claim 15, wherein the administration of radiation is performed after administration of the compound or a crystalline salt thereof. 16. The method of claim 16, wherein the administration of radiation is performed both before and after administration of the compound or a crystalline salt thereof. The method of any one of claims 1-17, further comprising administering one or more additional therapeutic agents. The method of any one of claims 1-18, wherein administration of the compound or crystalline salt thereof reduces or alleviates one or more signs or symptoms associated with DIPG. One or more of the above signs or symptoms may be changes in conversation or conversation patterns, loss of ability to move one side of the subject's face or body, loss of balance, loss of coordination, walking or motor problems, visual problems. 19. The method of claim 19, wherein the method is selected from the group consisting of hearing problems, headache, nausea, vomiting, abnormal drowsiness, altered energy levels, behavioral changes, and altered school performance. The method according to any one of claims 1 to 20, wherein administration of the compound or a crystalline salt thereof realizes a hate-free survival time. The hateless survival is one month or longer, two months or longer, three months or longer, four months or longer, five months or more. Long, 6 months or longer, 7 months or longer, 8 months or longer, 9 months or longer, 10 months or longer, 11 months 21. The method of claim 21, which is longer than that, one year or longer, two years or longer, three years or longer, or five years or longer. The method of any one of claims 1-22, further comprising one or more of tumor growth weight loss surgery or cerebrospinal fluid conversion. The method according to any one of claims 1 to 23, wherein the subject has a predetermined gene profile containing one or more mutations in the ACVR1 gene. 24. The method of claim 24, wherein the one or more mutations in the ACVR1 gene are activating mutations. One or more mutations in the ACVR1 gene encode an ACVR1 polypeptide containing amino acid substitutions at one or more amino acid residues selected from R206H, G328V, R258G, or a combination thereof. 25. The method of claim 25. 26. The method of claim 26, wherein the amino acid substitution in the ACVR1 polypeptide comprises R206H. The method according to any one of claims 1 to 27, wherein the compound or a crystalline salt thereof is orally administered. The method according to any one of claims 1 to 28, wherein the compound or a crystalline salt thereof is administered at a dose ranging from about 10 mg to about 320 mg per week. 29. The method of claim 29, wherein the dose ranges from about 30 mg to about 240 mg per week. 29. The method of claim 29, wherein the dose ranges from about 60 mg to about 180 mg per week. 29. The method of claim 29, wherein the dose ranges from about 30 mg to about 120 mg per week. 29. The method of claim 29, wherein the dose ranges from about 60 mg to about 120 mg per week. 29. The method of claim 29, wherein the dose is about 60 mg per week. 29. The method of claim 29, wherein the dose is about 90 mg per week. 29. The method of claim 29, wherein the dose is about 120 mg per week. 29. The method of claim 29, wherein the dose is about 180 mg per week. 29. The method of claim 29, wherein the dose is about 210 mg per week. 29. The method of claim 29, wherein the dose is about 240 mg per week. The compound or crystalline salt thereof is about 320 mg or less, about 240 mg or less, about 210 or less, about 180 or less, about 120 or less, about 90. The method according to any one of claims 1 to 28, which is administered at a weekly dose of about 60 or less, or about 30 or less. 40. The method of claim 40, wherein the dose is about 60 mg or less per week. 40. The method of claim 40, wherein the dose is about 90 mg or less per week. 40. The method of claim 40, wherein the dose is about 120 mg or less per week. 40. The method of claim 40, wherein the dose is about 180 mg or less per week. 40. The method of claim 40, wherein the dose is about 210 mg or less per week. 40. The method of claim 40, wherein the dose is about 240 mg or less per week. The method of any one of claims 29-46, wherein the dose is administered once a week. The dose is 2 or more partial doses, 3 or more partial doses, 4 or more partial doses, 5 or more partial doses over a week's course. The method of any one of claims 29-46, which is administered in a partial dose, 6 or more partial doses, or a daily partial dose. The method of any one of claims 29-48, wherein the subject is a pediatric patient and the dose is between about 80% and 100% of the dose range. 49. The method of claim 49, wherein the dose is adjusted to about 80%, 85%, 90%, or 95% of the dose range. 49. The method of claim 49, wherein the dose ranges from about 8 mg to about 320 mg per week. 49. The method of claim 49, wherein the dose ranges from about 24 mg to about 240 mg per week. 49. The method of claim 49, wherein the dose ranges from about 24 mg to about 120 mg per week. 49. The method of claim 49, wherein the dose ranges from about 48 mg to about 120 mg per week. 49. The method of claim 49, wherein the dose ranges from about 72 mg to about 120 mg per week. 49. The method of claim 49, wherein the dose ranges from about 96 mg to about 120 mg per week. The method of any one of claims 1-56, wherein the subject has a predetermined hepcidin level of at least about 0.1 ng / mL. 57. The method of claim 57, wherein the predetermined hepcidin level ranges from about 10 ng / mL to about 200 ng / mL. The method according to any one of claims 1 to 58, further comprising determining the hepcidin level of the subject after administration of the compound or a crystalline salt thereof. The method of any one of claims 1-59, further comprising determining the transferrin saturation level of the subject after administration of the compound or crystalline salt thereof. The method of claim 60, wherein the transferrin saturation level is less than about 50%. The method of claim 60, wherein the transferrin saturation level is less than about 45%. The method of claim 60, wherein the transferrin saturation level is less than about 40%. The method according to any one of claims 1 to 63, wherein the compound or a crystalline salt thereof is administered over one or more treatment cycles, each cycle comprising 4 weeks. 64. The method of claim 64, wherein the method further comprises one or more rest days between treatment cycles. The method of claim 65, wherein the rest day is selected from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks. A method for treating a disease or disorder that is susceptible to inhibition of ACVR1, said method is a therapeutically effective amount formula for a subject requiring treatment of a disease or disorder that is susceptible to inhibition of ACVR1. (2):

A method comprising administering a compound of, or a crystalline salt thereof, wherein the compound is administered at a dose ranging from about 10 mg to about 320 mg per week. 67. The method of claim 67, wherein the dose ranges from about 30 mg to about 240 mg per week. 67. The method of claim 67, wherein the dose ranges from about 60 mg to about 180 mg per week. 67. The method of claim 67, wherein the dose ranges from about 30 mg to about 120 mg per week. 67. The method of claim 67, wherein the dose ranges from about 60 mg to about 120 mg per week. 67. The method of claim 67, wherein the dose is about 60 mg per week. 67. The method of claim 67, wherein the dose is about 90 mg per week. 67. The method of claim 67, wherein the dose is about 120 mg per week. 67. The method of claim 67, wherein the dose is about 180 mg per week. 67. The method of claim 67, wherein the dose is about 210 mg per week. 67. The method of claim 67, wherein the dose is about 240 mg per week. The compound or crystalline salt thereof is about 320 mg or less, about 240 mg or less, about 210 or less, about 180 or less, about 120 or less, about 90. The method according to any one of claims 67 to 77, wherein the method is administered at a weekly dose of about 60 or less, or about 30 or less. The method of claim 78, wherein the dose is about 60 mg or less per week. The method of claim 78, wherein the dose is about 90 mg or less per week. The method of claim 78, wherein the dose is about 120 mg or less per week. The method of claim 78, wherein the dose is about 180 mg or less per week. The method of claim 78, wherein the dose is about 210 mg or less per week. The method of claim 78, wherein the dose is about 240 mg or less per week. The method of any one of claims 67-84, wherein the subject is a pediatric patient and the dose is between about 80% and 100% of the dose range. 85. The method of claim 85, wherein the dose is about 80%, 85%, 90%, or 95% of the dose range. 85. The method of claim 85, wherein the dose ranges from about 8 mg to about 320 mg per week. 85. The method of claim 85, wherein the dose ranges from about 24 mg to about 240 mg per week. 85. The method of claim 85, wherein the dose ranges from about 24 mg to about 120 mg per week. 85. The method of claim 85, wherein the dose ranges from about 48 mg to about 120 mg per week. 85. The method of claim 85, wherein the dose ranges from about 72 mg to about 120 mg per week. 85. The method of claim 85, wherein the dose ranges from about 96 mg to about 120 mg per week. The method of any one of claims 67-92, wherein the dose is administered once a week. The method of any one of claims 67-92, wherein the dose is administered in two partial doses over a one-week course. The method of any one of claims 67-92, wherein the dose is administered in three partial doses over a one-week course. The method of any one of claims 67-92, wherein the dose is administered in four partial doses over a one-week course. The method of any one of claims 67-92, wherein the dose is administered in 5 partial doses over a week of cool. The method of any one of claims 67-92, wherein the dose is administered in 6 partial doses over a week of cool. The method of any one of claims 67-92, wherein the dose is administered in daily partial doses. The method according to any one of claims 67 to 99, wherein the subject has a predetermined gene profile containing one or more mutations in the ACVR1 gene. The method of claim 100, wherein the one or more mutations in the ACVR1 gene are activating mutations. One or more mutations in the ACVR1 gene encode an ACVR1 polypeptide containing amino acid substitutions at one or more amino acid residues selected from R206H, G328V, R258G, or a combination thereof. The method according to claim 101. The method of claim 102, wherein the amino acid substitution in the ACVR1 polypeptide comprises R206H. The method according to any one of claims 67 to 103, wherein the compound or a crystalline salt thereof is orally administered. The disease or disorder is diffuse true pontine glioma, pontine tumor histologically diagnosed as grade II to IV invasive glioma, solid tumor, progressive ossifying fibrodysplasia, and chronic disease. The method of any one of claims 67-104, which is selected from one or more of anemia. The method according to claim 105, wherein the compound or a crystalline salt thereof is administered as a solid dose preparation. The method according to claim 105, wherein the compound or a crystalline salt thereof is administered as a liquid dose preparation. The method of any one of claims 67-107, wherein the subject is monitored for hepcidin levels to determine any adjustment of the dose. The method of any one of claims 67-108, wherein the subject is monitored for accumulation of the compound in one or more organs. The method according to any one of claims 67 to 109, wherein the crystalline salt is an acid addition salt. The method according to claim 110, wherein the acid addition salt is a hydrochloride salt. The method of claim 111, wherein the hydrochloride salt is monovalent. The method according to any one of claims 110 to 112, wherein the crystalline salt form is anhydrous. One or more pharmaceutically acceptable excipients and formula (2):

An oral solid pharmaceutical composition comprising the compound of the above or a crystalline salt thereof, wherein the compound is formulated with a titer of between about 5 mg and about 125 mg with respect to the weight of the free base. The pharmaceutical composition according to claim 114, wherein the crystalline salt is an acid addition salt. The pharmaceutical composition according to claim 115, wherein the acid addition salt is a hydrochloride salt. The pharmaceutical composition according to claim 116, wherein the hydrochloride salt is monovalent. The pharmaceutical composition according to any one of claims 115 to 117, wherein the crystalline salt form is anhydrous. The pharmaceutical composition according to any one of claims 114 to 118, wherein the pharmaceutical composition is a gelatin capsule. The pharmaceutical composition according to claim 119, wherein the gelatin capsule has a titer of (i) 5 mg, (ii) 25 mg, or (iii) 125 mg relative to the weight of the free base. 119. The pharmaceutical composition according to claim 119, wherein the gelatin capsule is (i) 30 mg, (ii) 60 mg, (iii) 90 mg, or (iv) 120 mg based on the weight of the free base. Any of claims 114-121, wherein one or more pharmaceutical excipients are selected from microcrystalline cellulose, lactose monohydrate, sodium croscarmellose, magnesium stearate, or a combination thereof. The pharmaceutical composition according to item 1. Equation (2):

With a compound of or a crystalline salt thereof;
(I) One or more buffers;
(Ii) One or more preservatives as needed;
(Iii) One or more solvents as needed;
An oral liquid pharmaceutical composition comprising (iv) one or more flavoring agents as needed; and (v) one or more additional pH regulators as needed. The pharmaceutical composition according to claim 123, wherein the crystalline salt is an acid addition salt. The pharmaceutical composition according to claim 124, wherein the acid addition salt is a hydrochloride salt. The pharmaceutical composition according to claim 125, wherein the hydrochloride salt is monovalent. The pharmaceutical composition according to any one of claims 124 to 126, wherein the crystalline salt form is anhydrous. The pharmaceutical composition according to any one of claims 123 to 127, wherein the composition has a pH between about 2.0 and about 5.0. The pharmaceutical composition of claim 128, wherein the composition has a pH between about 2.0 and about 3.5. The pharmaceutical composition according to claim 128, wherein the composition has a pH of about 2.0. The pharmaceutical composition according to any one of claims 123 to 130, wherein the buffer is selected from citric acid, tartaric acid, malic acid, or acetic acid. The pharmaceutical composition according to claim 131, wherein the buffer is malic acid. The pharmaceutical composition according to claim 132, wherein the malic acid is DL-malic acid. The pharmaceutical composition according to any one of claims 123 to 133, which comprises one or more preservatives. The pharmaceutical composition according to claim 134, wherein the preservative is selected from benzoic acid, sodium benzoate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, or propylene glycol. The pharmaceutical composition according to claim 135, wherein the preservative is benzoic acid. The pharmaceutical composition according to claim 136, wherein the benzoic acid is a preservative and a buffer. The pharmaceutical composition according to any one of claims 123 to 137, which comprises one or more flavoring agents. The pharmaceutical composition according to claim 138, wherein the flavoring agent is selected from sucralose, glycerin, cyclodextrin, HP-β-cyclodextrin, α-cyclodextrin, β-cyclodextrin, or a combination thereof. The pharmaceutical composition according to claim 138, wherein the flavoring agent is a combination of HP-β-cyclodextrin and sucralose. The pharmaceutical composition according to any one of claims 123 to 140, wherein the composition contains the compound of the formula (2) or a crystalline salt thereof at a concentration of about 10 mg / mL. The pharmaceutical composition according to any one of claims 123 to 141, wherein the composition contains malic acid at a concentration of up to about 6.7 mg / mL. The pharmaceutical composition according to claim 142, wherein the composition comprises malic acid at a concentration of about 1.3 mg / mL. The pharmaceutical composition according to any one of claims 123 to 143, wherein the composition comprises HP-β-cyclodextrin at a concentration of up to about 300 mg / mL. The pharmaceutical composition according to claim 144, wherein the composition comprises HP-β-cyclodextrin at a concentration of up to about 150 mg / mL. The pharmaceutical composition according to any one of claims 123 to 145, wherein the composition comprises sucralose at a concentration of up to about 2.0 mg / mL. The pharmaceutical composition according to claim 146, wherein the composition comprises sucralose at a concentration of about 1.0 mg / mL. The pharmaceutical composition according to any one of claims 123 to 147, wherein the composition contains benzoic acid at a concentration of up to about 3.0 mg / mL. The pharmaceutical composition according to claim 148, wherein the composition comprises benzoic acid at a concentration of up to about 2.0 mg / mL. The pharmaceutical composition according to any one of claims 123 to 149, wherein the pH is adjusted to about 2.0 with hydrochloric acid. The pharmaceutical composition according to any one of claims 123 to 150, wherein the solvent is water. Compound (2)

N ⁴ - (2,2'-bipyridine-3-yl) ^-N 2 - crystalline form of (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) salts of pyrimidine-2,4-diamine .. The crystalline form of claim 152, wherein the salt is a pharmaceutically acceptable salt. The crystalline form of claim 153, wherein the pharmaceutically acceptable salt is an HCl salt. The crystal form according to any one of claims 152 to 154, which comprises form A. The crystal form according to any one of claims 152 to 154, which is essentially the same as the form A. The crystalline form according to claim 155 or 156, wherein the form A is substantially free of impurities. Of (3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2,4-diamine anhydrous hydrochloride, - N ⁴ - (2,2'- bipyridine-3-yl) ^-N 2 Compound form A. N, characterized by an x-ray diffraction pattern (XRPD) containing one or more 2θ values selected from 13.53, 16.14, 17.67, 18.38, 24.96, and 28.18. ⁴ - (2,2'-bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin-1-yl) phenyl) compound form of pyrimidine-2,4-diamine in anhydrous hydrochloride A. A form according to claim 159, wherein the form features two or more of the listed 2θ values. A form according to claim 159, wherein the form is characterized by three or more of the listed 2θ values. A form according to claim 159, wherein the form features four or more of the listed 2θ values. A form according to claim 159, wherein the form is characterized by five or more of the listed 2θ values. A form according to claim 159, wherein the form comprises all six of the listed 2θ values. A form according to any one of claims 157 to 164, further comprising one or more 2θ values selected from 6.71, 19.25, 23.98, and 29.60. A form according to claim 165, wherein the form comprises two or more of the listed 2θ values. A form according to claim 165, wherein the form features three or more of the listed 2θ values. A form according to claim 165, wherein the form comprises all four of the listed 2θ values. The X-ray powder diffractometer uses the X-ray wavelength of Cu kα, Kα1 (Å): 1.540598, Kα2 (Å): 1.5444426, and has a Kα2 / Kα1 intensity ratio of 0.50, and X-rays. The form A according to any one of claims 158 to 168, wherein the tube is set to 45 kV, 40 mA and used in the reflection mode. The form A according to any one of claims 158 to 169, wherein the 2θ value is within ± 0.2 2θ. And wherein Figure 12 is substantially the same x-ray diffraction pattern ^{(XRPD), N 4 - (} 2,2'- bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin Compound form A of -1-yl) phenyl) pyrimidine-2,4-diamine anhydride. 196.2 ° C., characterized by endotherm at one or more of 214.8 ° C., and 274.0 ^℃, N 4 - (2,2'- bipyridine-3-yl) ^-N 2 - ( Compound form A of 3-methoxy-4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2,4-diamine anhydride. A form A of claim 172, further characterized by peak endotherm at one or more of 198.9 ° C., 218.0 ° C., and 275.9 ° C. A form A of claim 172 or 173, further characterized by a starting temperature of 274.0 ° C. A form according to any one of claims 172 to 174, further characterized by a weight loss of 1.7% up to 150 ° C. Figure 15 is substantially characterized in the same TGA-DSC thermogram ^and, N 4 - (2,2'-bipyridine-3-yl) ^-N 2 - (3- methoxy-4- (4-methylpiperazin -1 -Il) Phenyl) Pyrimidine-2,4-Diamine Anhydrous Hydrochloride Compound Form A. A pharmaceutical composition comprising the crystalline form according to any one of claims 152 to 176. The pharmaceutical composition according to claim 176, as a solid-dose formulation. The oral solid pharmaceutical composition according to any one of claims 114 to 122, wherein the compound is in the crystalline form according to any one of claims 152 to 176. The pharmaceutical composition according to claim 176, as a liquid-dose formulation. The oral liquid pharmaceutical composition according to any one of claims 123 to 151, wherein the compound is in the crystalline form according to any one of claims 152 to 176. The method according to any one of claims 1 to 113, wherein the compound is in the crystalline form according to any one of claims 152 to 176.

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